Search

Blindness early in life induces permanent alterations in brain anatomy, including reduced surface area of primary visual cortex (V1). Bilateral enucleation early in development causes greater reductions in primary visual cortex surface area than at later times. However, the time at which cortical surface area expansion is no longer sensitive to enucleation is not clearly established, despite being an important milestone for cortical development. Using histological and MRI techniques, we investigated how reductions in the surface area of V1 depends on the timing of blindness onset in rats, ferrets and humans. To compare data across species, we translated ages of all species to a common neuro-developmental event-time (ET) scale. Consistently, blindness during early cortical expansion induced large (~40%) reductions in V1 surface area, in rats and ferrets, while blindness occurring later had diminishing effects. Longitudinal measurements on ferrets confirmed that early enucleation disrupted cortical expansion, rather than inducing enhanced pruning. We modeled the ET associated with the conclusion of the effect of blindness on surface area at maturity (ETc), relative to the normal conclusion of visual cortex surface area expansion, (ETdev). A final analysis combining our data with extant published data confirmed that ETc occurred well before ETdev.

The efficacy of the recently approved drug fingolimod (FTY720) in multiple sclerosis patients results from the action of its phosphate metabolite on sphingosine-1-phosphate S1P1 receptors, while a variety of side effects have been ascribed to its S1P3 receptor activity. Although S1P and phospho-fingolimod share the same structural elements of a zwitterionic headgroup and lipophilic tail, a variety of chemotypes have been found to show S1P1 receptor agonism. Here we describe a study of the tolerance of the S1P1 and S1P3 receptors toward bicyclic heterocycles of systematically varied shape and connectivity incorporating acidic, basic, or zwitterionic headgroups. We compare their physicochemical properties, their performance in in vitro and in vivo pharmacokinetic models, and their efficacy in peripheral lymphocyte lowering. The campaign resulted in the identification of several potent S1P1 receptor agonists with good selectivity vs S1P3 receptors, efficacy at

Langguth et al. (2006) described a method for targeting primary auditory cortex (PAC) during transcranial magnetic stimulation (TMS) using the 10–20 electroencephalography system. Study aims were to measure the degree of accuracy in placing the TMS coil on the scalp overlying PAC using the 10–20 method and determine the extent to which accuracy depends on the hemisphere of the coil placement. Twelve participants underwent anatomical magnetic resonance imaging (MRI) of their head in a 3T scanner. Before imaging, a fiducial marker was placed on their scalp corresponding to the TMS coil position. MRI scans were analyzed to determine the distance from the fiducial marker to PAC for each participant. On average, the 10–20 method resulted in distances in the medial–lateral, anterior-posterior, and inferior-superior dimensions that were within a few millimeters (~ 4 mm) of each other between the left and right hemispheres. The fiducial marker was, on average, 10.4 mm superior and 10.8 mm posterior to the optimal scalp location that minimized the distance to PAC. Individual asymmetries and other systematic differences found in this study raise important considerations to keep in mind that might necessitate using an MRI-guided method of coil-positioning when targeting PAC for TMS.

Current research in connectomics highlights that self-organized functional networks or "communities" of cortical areas can be detected in the adult brain. This perspective may provide clues to mechanisms of treatment response in psychiatric conditions. Here we examine functional brain community topology based on resting-state fMRI in adult Attention-Deficit/Hyperactivity Disorder (ADHD; n = 22) and controls (n = 31). We sought to evaluate ADHD patterns in adulthood and their modification by short term stimulants administration. Participants with ADHD were scanned one or two weeks apart, once with medication and once without; comparison participants were scanned at one time-point. Functional connectivity was estimated from these scans and community detection applied to determine cortical network topology. Measures of change in connectivity profile were calculated via a graph measure, termed the Node Dissociation Index (NDI). Compared to controls, several cortical networks had atypical connectivity in adults with ADHD when withholding stimulants, as measured by NDI. In most networks stimulants significantly reduced, but did not eliminate, differences in the distribution of connections between key brain systems relative to the control sample. These findings provide an enriched model of connectivity in ADHD and demonstrate how stimulants may exert functional effects by altering connectivity profiles in the brain.

Background Neural correlates of stress regulation via the hypothalamic-pituitary-adrenal (HPA) axis have been identified, but little is known about how these apply to real-world interpersonal stress contexts such as mother-infant interaction. We extended stress regulation research by examining maternal neural activation to infant cry related to HPA regulation with their infants. Methods Twenty-two primiparous mothers listened to the cry sounds of their own 18-month-old infant and an unfamiliar infant and a control sound during functional magnetic resonance imaging scanning. Salivary cortisol was collected at four timepoints in a separate session involving the Strange Situation stressor. Cortisol trajectories were modeled with hierarchical linear modeling, and trajectory terms were used to predict neural response to own infant cry. Results Mothers who showed less HPA reactivity—indexed by trajectory curvature rather than level—showed increased activation to the cry of their infant relative to control sound across limbic/paralimbic and prefrontal circuits. These included periaqueductal gray, right insula, and bilateral orbitofrontal cortex as well as anterior cingulate-medial prefrontal cortex. Activations overlapped to some extent with previous HPA regulation findings and converged more extensively with circuits identified in other maternal response paradigms. Conclusions Maternal stress regulation involves both circuits found across stressor types (i.e., prefrontal) and areas unique to the mother-infant relationship (i.e., limbic/paralimbic). The shape of the HPA response trajectory of mothers was more important than the level of such response in defining stress-related neural correlates. Future research should consider dimensions of the stress context and of physiological trajectories to define stress-regulatory circuits.

Several recent studies have documented age-related changes in brain activity—less amygdala activity and higher prefrontal activity in response to emotional stimuli. Using functional magnetic resonance imaging (fMRI), we examined whether aging also affects the maintenance of activity to emotional stimuli and whether maintenance differs by the valence (negative, neutral and positive) of the pictures. Younger participants had a larger volume of activity in the amygdala but less in the prefrontal cortex than the old. The old showed more habituation to highly arousing negative but not positive or neutral stimuli in prefrontal cortex as compared to younger participants. Thus prefrontal cortex activity indexes emotion in the elderly, but not the young. Amplified prefrontal activity suggests elderly increase cognitive control for negative, highly arousing emotional stimuli, but it is not maintained. Taken together, age-related increases in prefrontal activity and reduced amygdala activity may underlie observed affective changes in aging.

Teenagers are often impulsive. In some cases this is a phase of normal development; in other cases impulsivity contributes to criminal behavior. Using functional magnetic resonance imaging, we examined resting-state functional connectivity among brain systems and behavioral measures of impulsivity in 107 juveniles incarcerated in a high-security facility. In less-impulsive juveniles and normal controls, motor planning regions were correlated with brain networks associated with spatial attention and executive control. In more-impulsive juveniles, these same regions correlated with the default-mode network, a constellation of brain areas associated with spontaneous, unconstrained, self-referential cognition. The strength of these brain–behavior relationships was sufficient to predict impulsivity scores at the individual level. Our data suggest that increased functional connectivity of motor-planning regions with networks subserving unconstrained, self-referential cognition, rather than those subserving executive control, heightens the predisposition to impulsive behavior in juvenile offenders. To further explore the relationship between impulsivity and neural development, we studied functional connectivity in the same motor-planning regions in 95 typically developing individuals across a wide age span. The change in functional connectivity with age mirrored that of impulsivity: younger subjects tended to exhibit functional connectivity similar to the more-impulsive incarcerated juveniles, whereas older subjects exhibited a less-impulsive pattern. This observation suggests that impulsivity in the offender population is a consequence of a delay in typical development, rather than a distinct abnormality.

A computational lead-hopping exercise identified compound 4 as a structurally distinct P2X(7) receptor antagonist. Structure-activity relationships (SAR) of a series of pyroglutamic acid amide analogues of 4 were investigated and compound 31 was identified as a potent P2X(7) antagonist with excellent in vivo activity in animal models of pain, and a profile suitable for progression to clinical studies.

Structure–activity relationships (SAR) of analogues of lead compound 1 were investigated and compound 16 was selected for further study in animal models of pain. Compound 16 was shown to be a potent antihyperalgesic agent in both the rat acute complete Freund’s adjuvant (CFA) model of inflammatory pain [Iadarola, M. J.; Douglass, J.; Civelli, O.; Naranjo, J. R. rain Res. 1988, 455, 205] and the knee joint model of chronic inflammatory pain [Wilson, A. W.; Medhurst, S. J.; Dixon, C. I.; Bontoft, N. C.; Winyard, L. A.; Brackenborough, K. T.; De Alba, J.; Clarke, C. J.; Gunthorpe, M. J.; Hicks, G. A.; Bountra, C.; McQueen, D. S.; Chessell, I. P. Eur. J. Pain 2006, 10, 537].

High-throughput screening identified compound 1 as a potent P2X(7) receptor antagonist suitable for lead optimisation. Structure-activity relationships (SAR) of a series of (1H-pyrazol-4-yl)acetamides were investigated and compound 32 was identified as a potent P2X(7) antagonist with enhanced potency and favourable physicochemical and pharmacokinetic properties.

Optimisation of a series of benzazepine sulfonamide hit compounds identified from high throughput screening led to the discovery of a new series of tractable, potent motilin receptor agonists.

Early onset blindness leads to a dramatic alteration in the way the world is perceived, a change that is detectable in the organization of the brain. Several studies have confirmed that blindness leads to functional alterations in occipital cortices that normally serve visual functions. These reorganized brain regions respond to a variety of tasks and stimuli, but their specific functions are unclear. In sighted individuals, several studies have reported preparatory activity in retinotopic areas, which enhances perceptual sensitivity. “Baseline shifts,” changes in activity associated with a cue predicting an upcoming event, provides a marker for attentional modulation. Here we demonstrate that, in early blind subjects, medial occipital areas produced significant blood oxygenation level-dependent (BOLD) responses to a cue signaling an auditory discrimination trial but not to a cue indicating a no-trial period. Furthermore, the amplitude of the BOLD response in the anterior calcarine sulcus of early blind subjects correlated with their discrimination performance on the auditory backward masking task. Preparatory BOLD responses also were present in auditory cortices, although they were more robust in blind than sighted control subjects. The pattern of response in visual areas is similar to preparatory effects observed during visual selective attention in sighted subjects and consistent with the hypothesis that the mechanisms implicated in visual attention continue to modulate occipital cortex in the early blind. A possible source of this top-down modulation may be the frontoparietal circuits that retain their connectivity with the reorganized occipital cortex and as a result influence processing of nonvisual stimuli in the blind.

Objective Ferumoxytol, an iron oxide nanoparticle that targets phagocytic cells, can be used in magnetic resonance imaging of malignant brain tumors and can be administered as a bolus, allowing dynamic imaging. Our objectives were to determine the optimum time of delayed contrast enhancement of ferumoxytol, and to compare ferumoxytol and gadolinium contrast agents for magnetic resonance angiography and perfusion. Methods Twelve patients with malignant brain tumors underwent serial magnetic resonance imaging multiple times up to 72 hours after ferumoxytol injection at both 1.5 and 3-T. The enhancement time course was determined for ferumoxytol and compared with a baseline gadolinium scan. Perfusion, time-of-flight and dynamic magnetic resonance angiography and T1-weighted scans were compared for the two agents. Results The lesions were detectable at all field strengths, even with an intraoperative 0.15-T magnet. Maximal ferumoxytol enhancement intensity was at 24 to 28 hours after administration, and the enhancing volume subsequently expanded with time into a non-gadolinium-enhancing, high T2-weighted signal region of tumor-infiltrated brain. Dynamic studies were assessed with both agents, indicating early vascular leak with gadolinium but not with ferumoxytol. Conclusion Our most important finding was that gadolinium leaks out of blood vessels early after injection, whereas ferumoxytol stays intravascular in the "early" phase, thereby increasing the accuracy of tumor perfusion assessment. As a magnetic resonance imaging contrast agent, ferumoxytol visualizes brain tumors at all field strengths evaluated, with delayed enhancement peaking at 24 to 28 hours after administration.

Small molecule antagonists of the vanilloid receptor TRPV1 (also known as VR1) are disclosed. Pyrrolidinyl ureas such as 8 and 15 (SB-705498) emerged as lead compounds following optimisation of the previously described urea SB-452533. Pharmacological studies using electrophysiological and FLIPR-Ca2+-based assays showed that compounds such as 8 and 15 were potent antagonists versus the multiple chemical and physical modes of TRPV1 activation (namely capsaicin, acid and noxious heat). Furthermore, 15 possessed suitable developability properties to enable progression of this compound into in vivo studies and subsequently clinical development.

For blind individuals, audition provides critical information for interacting with the environment. Individuals blinded early in life (EB) typically show enhanced auditory abilities relative to sighted controls as measured by tasks requiring complex discrimination, attention and memory. In contrast, few deficits have been reported on tasks involving auditory sensory thresholds (e.g., Yates, J.T., Johnson, R.M., Starz, W.J., 1972. Loudness perception of the blind. Audiology 11(5), 368-376; Starlinger, I., Niemeyer, W., 1981. Do the blind hear better? Investigations on auditory processing in congenital or early acquired blindness. I. Peripheral functions. Audiology 20(6), 503-509). A study of gap detection stands at odds with this distinction [Muchnik, C., Efrati, M., Nemeth, E., Malin, M., Hildesheimer, M., 1991. Central auditory skills in blind and sighted subjects. Scand. Audiol. 20(1), 19-23]. In the current investigation we re-examined gap detection abilities in the EB using a single-interval, yes/no method. A group of younger sighted control individuals (SCy) was included in the analysis in addition to EB and sighted age matched control individuals (SCm) in order to examine the effect of age on gap detection performance. Estimates of gap detection thresholds for EB subjects were nearly identical to SCm subjects and slightly poorer relative to the SCy subjects. These results suggest some limits on the extent of auditory temporal advantages in the EB.

This work examines the inter-relationship between the unbound drug fractions in blood and brain homogenate, passive membrane permeability, P-glycoprotein (Pgp) efflux ratio, and log octanol/water partition coefficients (cLogP) in determining the extent of central nervous system (CNS) penetration observed in vivo. The present results demonstrate that compounds often considered to be Pgp substrates in rodents (efflux ratio greater than 5 in multidrug resistant Madin-Darby canine kidney cells) with poor passive permeability may still exhibit reasonable CNS penetration in vivo; i.e., where the unbound fractions and nonspecific tissue binding act as a compensating force. In these instances, the efflux ratio and in vitro blood-brain partition ratio may be used to predict the in vivo blood-brain ratio. This relationship may be extended to account for the differences in CNS penetration observed in vivo between mdr1a/b wild type and knockout mice. In some instances, cross-species differences that might initially seem to be related to differing transporter expression can be rationalized from knowledge of unbound fractions alone. The results presented in this article suggest that the information exists to provide a coherent picture of the nature of CNS penetration in the drug discovery setting, allowing the focus to be shifted away from understanding CNS penetration toward the more important aspect of understanding CNS efficacy.

Human speech carries both linguistic content and information about the speaker's identity and affect. While neuroimaging has been used extensively to study verbal memory, there has been little attention to the neural basis of memory for voices. Evidence from studies of aphasia and auditory agnosia suggests that voice memory may rely on anatomically distinct areas in the right temporal and parietal lobes regions, but there is little data on the broader neural systems involved in voice memory. The present study tested the hypothesis that the neural systems involved in voice memory are functionally distinct from the systems involved in word recognition and are primarily located in the right cerebral hemisphere. Subjects performed two-back tasks in which they were required to alternately remember the voices speaking (Voice condition), and the words they produced (Word condition). A tone memory condition was also included, as a non-speech comparison. The contrast between the Voice and Word conditions revealed greater Voice-related effects in left temporal, right frontal and right medial parietal areas, while the Word-related effects appeared in left frontal and bilateral parietal areas. These findings map out a partially right-lateralized fronto-parietal network associated with voice memory, which can be distinguished from predominantly left-hemisphere regions associated with verbal working memory. These results provide further evidence that distinct neural systems are associated with the carrier waves of speech and word identity.

(6-((R)-2-{2-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-ethyl}-pyrrolidine-1-sulphonyl)-1H-indole hydrochloride) (SB-656104-A), a novel 5-hydroxytryptamine (5-HT7) receptor antagonist, potently inhibited [3H]-SB-269970 binding to the human cloned 5-HT7(a) (pKi 8.7±0.1) and 5-HT7(b) (pKi 8.5±0.2) receptor variants and the rat native receptor (pKi 8.8±0.2). The compound displayed at least 30-fold selectivity for the human 5-HT7(a) receptor versus other human cloned 5-HT receptors apart from the 5-HT1D receptor (∼10-fold selective). SB-656104-A antagonised competitively the 5-carboxamidotryptamine (5-CT)-induced accumulation of cyclic AMP in h5-HT7(a)/HEK293 cells with a pA2 of 8.5. Following a constant rate iv infusion to steady state in rats, SB-656104 had a blood clearance (CLb) of 58±6 ml min−1 kg−1 and was CNS penetrant with a steady-state brain : blood ratio of 0.9 : 1. Following i.p. administration to rats (10 mg kg−1), the compound displayed a t1/2 of 1.4 h with mean brain and blood concentrations (at 1 h after dosing) of 0.80 and 1.0 μM, respectively. SB-656104-A produced a significant reversal of the 5-CT-induced hypothermic effect in guinea pigs, a pharmacodynamic model of 5-HT7 receptor interaction in vivo (ED50 2 mg kg−1). SB-656104-A, administered to rats at the beginning of the sleep period (CT 0), significantly increased the latency to onset of rapid eye movement (REM) sleep at 30 mg kg−1 i.p. (+93%) and reduced the total amount of REM sleep at 10 and 30 mg kg−1 i.p. with no significant effect on the latency to, or amount of, non-REM sleep. SB-269970-A produced qualitatively similar effects in the same study. In summary, SB-656104-A is a novel 5-HT7 receptor antagonist which has been utilised in the present study to provide further evidence for a role for 5-HT7 receptors in the modulation of REM sleep. British Journal of Pharmacology (2003) 139, 705–714. doi:10.1038/sj.bjp.0705290

A 2,000-m time-trial performance, aerobic capacity, and anaerobic capacity were assessed in 16 trained oarsmen after sprint interval training (SIT) replaced a portion of an endurance-based training program (EBTSIT) vs. an endurance-based program alone (EBTAlone). The EBTSIT involved 10 SIT sessions over 4 weeks, in addition to 12 continuous exercise sessions, 2 anaerobic threshold exercise sessions, and 4 strength training sessions. The EBTAlone consisted of 20 continuous, 6 anaerobic threshold, 2 interval exercise sessions, and 8 strength training sessions. Time-trial performance (2,000-m erg performance) improved with EBTSIT (baseline = 414.6 ± 18.5, post = 410.6 ± 17.5 seconds; p < 0.001) but only approached significance in EBTAlone (baseline = 413.0 ± 27.7, post = 411.4 ± 27.9 seconds; p = 0.06). In a 60-second "all-out" anaerobic capacity test, peak power output (PPO) increased significantly with EBTSIT (PPO: EBTSIT: baseline = 566 ± 82, post = 623 ± 60 W; p = 0.02) but not with EBTAlone (EBTAlone: baseline = 603 ± 81, post = 591 ± 123 W; p = 0.59). Changes in average power output (APO) also approached significance (p = 0.07) (APO: EBTSIT: baseline = 508 ± 48, post = 530 ± 52 W; EBTAlone: baseline = 532 ± 55, post = 533 ± 68 W). Neither group experienced any change in aerobic capacity ((Equation is included in full-text article.)or ventilatory threshold; p ≥ 0.16). We conclude that replacing a portion of EBT with SIT can improve both 2,000-m erg performance and anaerobic capacity, while maintaining aerobic fitness in trained oarsmen. Incorporating SIT within endurance training programs may be useful during periods of low-volume training, to improve performance without sacrificing aerobic capacity.

The authors reported that a subgroup of schizophrenic patients performed well on a tone serial position task but was impaired on an auditory word serial position task (Wexler, Stevens, Bowers, Cerniak, & Goldman-Rakic, 1998). This study assessed 30 schizophrenic and 32 controls (matched for comparable tone discrimination) on 4 versions of the verbal serial position tasks and 2 tone serial position tasks. Patients performed poorly on all verbal tasks but performed comparably to controls when tones served as stimuli. Proactive interference and visual presentation further compounded the verbal deficits. Deficits persisted with pronounceable nonword stimuli. These findings provide evidence of specific deficits in language-related processing, although the authors could not rule out the possibility that the differential effects that were observed between the tone and word tasks, and particularly among the verbal tasks, may result from differing discriminating power of the different tests.

Functional magnetic resonance imaging (fMRI) was used to investigate the spatial distribution of cortical activation in frontal and parietal lobes during auditory and visual oddball tasks in 10 healthy subjects. The purpose of the study was to compare activation within auditory and visual modalities and identify common patterns of activation across these modalities. Each subject was scanned eight times, four times each for the auditory and visual conditions. The tasks consisted of a series of trials presented every 1500 ms of which 4-6% were target trials. Subjects kept a silent count of the number of targets detected during each scan. The data were analyzed by correlating the fMRI signal response of each pixel to a reference hemodynamic response function that modeled expected responses to each target stimulus. The auditory and visual targets produced target-related activation in frontal and parietal cortices with high spatial overlap particularly in the middle frontal gyrus and in the anterior cingulate. Similar convergence zones were detected in parietal cortex. Temporal differences were detected in the onset of the activation in frontal and parietal areas with an earlier onset in parietal areas than in the middle frontal areas. Based on consistent findings with previous event-related oddball tasks, the high degree of spatial overlap in frontal and parietal areas appears to be due to modality independent or amodal processes related to procedural aspects of the tasks that may involve memory updating and non-specific response organization.

An auditory match-to-position (AMTP) task was developed to compare the effects of medial thalamic (L-IML) and prefrontal cortical (MW) lesions on the ability of rats to perform conditional discriminations with and without memory delays. Both lesions affected AMTP when there was no delay, and these impairments were not exacerbated when memory delays were imposed. The MW group performed normally, whereas the L-IML group was impaired in learning a go/no-go discrimination based on the same auditory stimuli as those used for AMTP. These findings are consistent with other evidence that the medial prefrontal cortex is critical for conditional associative learning when the same response alternatives are presented repeatedly across trials. The impairments observed for AMTP when there was no memory delay suggest that the effects of these lesions on the rate of forgetting may have been masked by the effects of these lesions on nonmnemonic aspects of the AMTP task.

Purpose. To determine the permeability characteristics of the rat air pouch model of inflammation using permeability extremes within which the NSAIDs S[ + ] ibuprofen, piroxicam and diclofenac could be evaluated.

Difficulty with selective attention is a frequent complaint of adult patients with ADHD, but selective attention tasks have not provided robust evidence of attentional dysfunction in this group. Two experiments examine this puzzle by distinguishing between failures of spatial selection and problems due to sensitivity to perceptual interference. In Experiment 1, we measured the level of perceptual interference generated by targets in crowded displays with nearby distractors by comparing luminance thresholds in both distractor-present (noise) and distractor-absent (clean) displays. ADHD and control participants had comparable thresholds for clean displays, but ADHD individuals had elevated thresholds to crowded displays. These effects could be explained in two distinct ways. Deficits may have arisen from amplified visual interference in the noise condition, or from abnormalities in top-down attentional processes that reduce visual interference. Experiment 2 adjusted for individual perceptual differences with clean and noise displays, before measuring visual interference resolution at attended versus unattended locations. ADHD and control groups had comparable interference resolution at attended locations. These results suggest that perceptual interference rather than spatial attention deficits may account for some deficits in ADHD. This putative deficit in sensory function highlights a potential early-stage perceptual processing deficit in ADHD distinct from selective attention.

The regulation of mood occurs at multiple conscious and unconscious levels. A conscious, self-reflective level of mood regulation is identified as one in which we are aware of both our mood and our thoughts about that mood. Thoughts such as "I shouldn′t feel this way′ and "I′m thinking good things to cheer up′ come to mind at that level. Study 1 employs a multiple-domain, factor-analytic approach to determine the dimensions that best describe such reflective experience. Study 2′s analyses cross-validate findings from Study 1 and correlate the major meta-experience factors with personality scales; several experiential styles of metaexperience are described.

N-(3-Fluorophenyl)-1-[(4-([(3S)-3-methyl-1-piperazinyl]methyl)phenyl)acetyl]-4-piperidinamine 12 (GSK962040) is a novel small molecule motilin receptor agonist. It possesses excellent activity at the recombinant human motilin receptor and also at the native rabbit motilin receptor where its agonist activity results in potentiation of the amplitude of neuronal-mediated contractions of isolated gastric antrum tissue. Compound 12 also possesses highly promising pharmacokinetic profiles in both rat and dog, and these results, in combination with further profiling in human native tissue and an in vivo model of gastrointestinal transit in the rabbit, have led to its selection as a candidate for further development.

A novel series of [4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)-2-pyrimidine-based cyclooxygenase-2 (COX-2) inhibitors, which have a different arrangement of substituents compared to the more common 1,2-diarylheterocycle based molecules, have been discovered. For example, 2-(butyloxy)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (47), a member of the 2-pyrimidinyl ether series, has been shown to be a potent and selective inhibitor with a favourable pharmacokinetic profile, high brain penetration and good efficacy in rat models of hypersensitivity.

The penetration of drugs into the central nervous system is a composite of both the rate of drug uptake across the blood-brain barrier and the extent of distribution into brain tissue compartments. Clinically, positron emission tomography (PET) is the primary technique for deriving information on drug biodistribution as well as target receptor occupancy. In contrast, rodent models have formed the basis for much of the current understanding of brain penetration within pharmaceutical Drug Discovery. Linking these two areas more effectively would greatly improve the translation of candidate compounds into therapeutic agents. This paper examines two of the major influences on the extent of brain penetration across species, namely plasma protein binding and brain tissue binding. An excellent correlation was noted between unbound brain fractions across species (R(2) > 0.9 rat, pig, and human, n = 21), which is indicative of the high degree of conservation of the central nervous system environment. In vitro estimates of human brain-blood or brain-plasma ratios of marketed central nervous system drugs and PET tracers agree well with in vivo values derived from clinical PET and post-mortem studies. These results suggest that passive diffusion across the blood-brain barrier is an important process for many drugs in humans and highlights the possibility for improved prediction of brain penetration across species.

Optimisation of urea (5), identified from high throughput screening and subsequent array chemistry, has resulted in the identification of pyridine carboxamide (33) which is a potent motilin receptor agonist possessing favourable physicochemical and ADME profiles. Compound (33) has demonstrated prokinetic-like activity both in vitro and in vivo in the rabbit and therefore represents a promising novel small molecule motilin receptor agonist for further evaluation as a gastroprokinetic agent.

Methamphetamine (MA)-dependent individuals prefer smaller immediate over larger delayed rewards in delay discounting (DD) tasks. Human and animal data implicate ventral (amygdala, ventral striatum, ventrolateral prefrontal cortex insula) and dorsal (dorsolateral prefrontal cortex, dorsal anterior cingulate cortex and posterior parietal cortex) systems in DD decisions. The ventral system is hypothesized to respond to the salience and immediacy of rewards while the dorsal system is implicated in the process of comparison and choice.We used functional Magnetic Resonance Imaging to probe the neural correlates of DD in 19 recently abstinent MA-dependent patients and 17 age- and gender-matched controls.Hard DD choices were associated with greatest activation in bilateral middle cingulate, posterior parietal cortex (PPC), and the right rostral insula. Control subjects showed more activation than MA patients bilaterally in the precuneus and in the right caudate nucleus, anterior cingulate cortex (ACC), and dorsolateral prefrontal cortex (DLPFC). Magnitude of discounting was correlated with activity in the amygdala, DLPFC, posterior cingulate cortex and PPC.Our findings were consistent with a model wherein dorsal cognitive systems modulate the neural response of ventral regions. Patients addicted to MA, who strongly prefer smaller immediate over larger delayed rewards, activate the dorsal cognitive control system in order to overcome their preference. Activation of the amygdala during choice of delayed rewards was associated with a greater degree of discounting, suggesting that heavily discounting MA-dependent individuals may be more responsive to the negative salience of delayed rewards than controls.

6-Phenylnicotinamide (2) was previously identified as a potent TRPV1 antagonist with activity in an in vivo model of inflammatory pain. Optimization of this lead through modification of both the biaryl and heteroaryl components has resulted in the discovery of 6-(4-fluorophenyl)-2-methyl-N-(2-methylbenzothiazol-5-yl)nicotinamide (32; SB-782443) which possesses an excellent overall profile and has been progressed into pre-clinical development.

We used functional magnetic resonance imaging (fMRI) to examine responses within auditory cortical fields during the passive listening of pure tone (PT) and frequency modulated (FM) stimuli in seven early blind (EB), five late blind (LB) and six sighted control (SC) individuals. Subjects were scanned using a "sparse sampling" imaging technique while listening to PT and FM sounds presented at either low (400 Hz) or high (4 kHz) center frequencies. When high tones were directly compared to low tones, the resulting activation maps showed a general tonotopic organization within the superior and middle temporal lobes at statistically significant thresholds for the SC and LB groups while the EB group showed a comparable tonotopic organization but only at statistically non-significance thresholds. A contrast of all tonal stimuli to a quiet baseline similarly revealed significantly less signal volume in the EB than in either the LB or SC groups. These results suggest that EB does not alter inherent patterns of tonotopic organization but rather, under low-demand listening conditions, results in a more efficient processing of simple auditory stimuli within the early stages of the auditory hierarchy. While these effects must be interpreted cautiously due to the small sample sizes, they indicate that functional responses in auditory cortical areas are altered by visual deprivation and that intramodal auditory plasticity may underlie previously reported auditory advantages observed in the blind.

Self-report surveys and behavioral tasks indicate greater risk-taking behavior in adolescents as compared with adults. However, the underlying causes of these behavioral differences remain unclear. The present study examined the possibility that adolescents may be more susceptible to immediate positive and negative outcomes than adults. We compared the behavior of adolescents and adults on a modified version of the Balloon Analogue Risk Task (Lejuez et al., 2002). The task required that participants press a button to "inflate" a series of balloons on a computer screen. Balloons inflated until either the participant released the button ("saved" balloons) or the balloon "burst." Accumulated points increased as the duration of the buttonpress increased; however, simultaneously, the likelihood that the balloon would burst also increased. Adolescents inflated balloons to a larger size prior to saving them than adults did, suggesting relatively higher levels of risk taking, although the adolescents' behavior was not uniformly risk prone. Further, in comparison with adults, behavior in adolescents was more influenced by whether a balloon was saved or had burst on the preceding trial, suggesting that sensitivity to immediate consequences is one mechanism that underlies the observed difference in risk taking.

Visual deprivation early in life results in occipital cortical responsiveness across a broad range of perceptual and cognitive tasks. In the reorganized occipital cortex of early blind (EB) individuals, the relative lack of specificity for particular sensory stimuli and tasks suggests that attention effects may play a prominent role in these areas. We wished to establish whether occipital cortical areas in the EB were responsive to stimuli across sensory modalities (auditory, tactile) and whether these areas maintained or altered their activity as a function of selective attention. Using a three-stimulus oddball paradigm and event-related functional magnetic resonance imaging, auditory and tactile tasks presented separately demonstrated that several occipital regions of interest (ROIs) in the EB, but not sighted controls (SCs), responded to targets and task-irrelevant distracter stimuli of both modalities. When auditory and tactile stimuli were presented simultaneously with subjects alternating attention between sensory streams, only the calcarine sulcus continued to respond to stimuli in both modalities. In all other ROIs, responses to auditory targets were as large or larger than those observed in the auditory-alone condition, but responses to tactile targets were attenuated or abolished by the presence of unattended auditory stimuli. Both auditory and somatosensory cortices responded consistently to auditory and tactile targets, respectively. These results reveal mechanisms of orienting and selective attention within the visual cortex of EB individuals and suggest that mechanisms of enhancement and suppression interact asymmetrically on auditory and tactile streams during bimodal sensory presentation.

What happens in vision-related cortical areas when congenitally blind (CB) individuals orient attention to spatial locations? Previous neuroimaging of sighted individuals has found overlapping activation in a network of frontoparietal areas including frontal eye fields (FEF), during both overt (with eye movement) and covert (without eye movement) shifts of spatial attention. Since voluntary eye movement planning seems irrelevant in CB, their FEF neurons should be recruited for alternative functions if their attentional role in sighted individuals is only due to eye movement planning. Recent neuroimaging of the blind has also reported activation in medial occipital areas, normally associated with visual processing, during a diverse set of non-visual tasks, but their response to attentional shifts remains poorly understood. Here, we used event-related fMRI to explore FEF and medial occipital areas in CB individuals and sighted controls with eyes closed (SC) performing a covert attention orienting task with endogenous verbal cues and spatialized auditory targets. We found robust stimulus-locked FEF activation of all CB subjects, similar to and stronger than in SC, suggesting that FEF plays a role in endogenous orienting of covert spatial attention even in individuals in whom voluntary eye movements are irrelevant. We also found robust activation in bilateral medial occipital cortex in CB but not in SC subjects. The response decreased below baseline following endogenous verbal cues but increased following auditory targets, suggesting that the medial occipital area in CB does not directly engage during cued orienting of attention but may be recruited for processing of spatialized auditory targets.

Starting from the high throughput screening hit (3), novel N-tetrahydroquinolinyl, N-quinolinyl and N-isoquinolinyl carboxamides have been identified as potent antagonists of the ion channel TRPV1. The N-quinolinylnicotinamide (46) showed excellent potency at human, guinea pig and rat TRPV1, a favourable in vitro DMPK profile and activity in an in vivo model of inflammatory pain.

Early-onset blindness (EB) produces measurable advantages in auditory perception, attention, memory and language. Neville and Bavelier [Neville, H. J., & Bavelier, D. (2001) Variability of developmental plasticity. In J. L. McClelland, R. S. Siegler (Eds.) Mechanisms of cognitive development: Behavioral and ellon symposia on cognition (pp. 271–301)] hypothesized that faster temporal processing underlies many auditory compensatory effects in the blind. We tested this hypothesis by comparing early-onset blind individuals and sighted counterparts (SC) by assessing their rates of perceptual consolidation, the accurate perceptual representation of auditory stimuli. Firstly, we first tested both groups on a temporal-order judgment task (TOJ). EB subjects had significantly lower TOJ thresholds than the SC subjects. Secondly, we assessed perceptual consolidation speed using auditory backward masking tasks, taking into account individual TOJ thresholds. Discrimination performance was unaffected at all mask delays in the EB group while the SC subjects needed a mask delay of 160 ms to perform comparably. A backward masking task using single tone stimuli found no differences between the EB and SC groups any mask delay. A simultaneous masking task demonstrated that the mask effectively impaired discrimination in EB subjects at sensory stages. These results suggest that advantages in perceptual consolidation may reflect a mechanism responsible for the short response times and better performance reported in early blind individuals across a number of complex auditory tasks.

GW406381 (8), currently undergoing clinical evaluation for the treatment of inflammatory pain is a member of a novel series of 2,3-diaryl-pyrazolo[1,5-b]pyridazine based cyclooxygenase-2 (COX-2) inhibitors, which have been shown to be highly potent and selective. Several examples of the series, in addition to possessing favourable pharmacokinetic profiles and analgesic activity in vivo, have also demonstrated relatively high brain penetration in the rat compared with the clinically available compounds, which may ultimately prove beneficial in the treatment of pain.

Small molecule antagonists of the vanilloid receptor 1 (TRPV1, also known as VR1) are disclosed. Ureas such as 5 (SB-452533) were used to explore the structure activity relationship with several potent analogues identified. Pharmacological studies using electrophysiological and FLIPR Ca2+ based assays showed compound 5 was an antagonist versus capsaicin, noxious heat and acid mediated activation of TRPV1. Study of a quaternary salt of 5 supports a mode of action in which compounds from this series cause inhibition via an extracellularly accessible binding site on the TRPV1 receptor.

1 (6-((R)-2-[2-[4-(4-Chloro-phenoxy)-piperidin-1-yl]-ethyl]-pyrrolidine-1-sulphonyl)-1H-indole hydrochloride) (SB-656104-A), a novel 5-hydroxytryptamine (5-HT(7)) receptor antagonist, potently inhibited [(3)H]-SB-269970 binding to the human cloned 5-HT(7(a)) (pK(i) 8.7+/-0.1) and 5-HT(7(b)) (pK(i) 8.5+/-0.2) receptor variants and the rat native receptor (pK(i) 8.8+/-0.2). The compound displayed at least 30-fold selectivity for the human 5-HT(7(a)) receptor versus other human cloned 5-HT receptors apart from the 5-HT(1D) receptor ( approximately 10-fold selective). 2 SB-656104-A antagonised competitively the 5-carboxamidotryptamine (5-CT)-induced accumulation of cyclic AMP in h5-HT(7(a))/HEK293 cells with a pA(2) of 8.5. 3 Following a constant rate iv infusion to steady state in rats, SB-656104 had a blood clearance (CL(b)) of 58+/-6 ml min(-1) kg(-1) and was CNS penetrant with a steady-state brain : blood ratio of 0.9 : 1. Following i.p. administration to rats (10 mg kg(-1)), the compound displayed a t(1/2) of 1.4 h with mean brain and blood concentrations (at 1 h after dosing) of 0.80 and 1.0 micro M, respectively. 4 SB-656104-A produced a significant reversal of the 5-CT-induced hypothermic effect in guinea pigs, a pharmacodynamic model of 5-HT(7) receptor interaction in vivo (ED(50) 2 mg kg(-1)). 5 SB-656104-A, administered to rats at the beginning of the sleep period (CT 0), significantly increased the latency to onset of rapid eye movement (REM) sleep at 30 mg kg(-1) i.p. (+93%) and reduced the total amount of REM sleep at 10 and 30 mg kg(-1) i.p. with no significant effect on the latency to, or amount of, non-REM sleep. SB-269970-A produced qualitatively similar effects in the same study. 6 In summary, SB-656104-A is a novel 5-HT(7) receptor antagonist which has been utilised in the present study to provide further evidence for a role for 5-HT(7) receptors in the modulation of REM sleep.

A focused SAR study around the previously reported selective 5-HT 7 receptor antagonist, SB-269970-A has resulted in the identification of a structurally related analogue having an improved pharmacokinetic profile. Replacement of the phenolic group in SB-269970-A with an indole moiety, and replacement of the piperidinyl 4-methyl group with a heterocyclic ring system proved to be the key changes leading to the identification of SB-656104-A.