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New compounds selective for α 1A -adrenoceptors in the prostate may offer enhanced efficacy for benign prostatic hyperplasia (BPH), with fewer side effects than current treatment. A-131701 (3-[2-((3aR,9bR)-cis-6-methoxy-2,3,3a,4,5,9b,hexanydro-[1H]-benz[e]isoindol-2-yl)ethyl]pyrido[3',4':4,5]thien [3,2-d]pyrimidine-2,4(1H,3H)-dione), from a novel class of benz[e]isolindole pyridothienopyrimidines and pyridothienopyrazines, is selective for α 1a - and α 1d -adrenoceptors in radioligand binding studies (0.22 nM at α 1a -, 0.97 nM at aid-) compared to α 1b -sites (2.5 nM) and in isolated tissue bioassays (pA 2 values of 8.9-9.0 for α 1A -receptors in rat vas deferens or canine prostate strips, 9.1 at α 1D -sites (rat aorta)), compared to 7.9 at α 1B -sites (rat spleen). A-131701 also potently blocked radioligand binding to α 1 -adrenoceptors in canine and human prostatic membranes, but was considerably weaker at α 2 -adrenoceptors. In isoflurane-anesthetized dogs, A-131701 antagonized epinephrine-induced increases in intraurethral pressure (IUP) with a pseudo-pA 2 value of 8.17. In spontaneously hypertensive rats, A-131701 caused transient decreases in mean arterial blood pressure (MABP) and transient tachycardia. The area under the curve (AUC 0→60 min) for the hypotensive response was dose-related, with a log index value for A-131701 of 5.33, suggesting a selectivity of >600-fold comparing IUP to MABP effects. In pentobarbital-anesthetized dogs, A-131701 was more potent in blocking phenylephrine (PHE)-induced increases in IUP (pseudo-pA 2 = 8.0) compared to concurrently measured MABP (pseudo-pA 2 = 7.2), or sixfold selective. Doses greater than 1,000 nmol/kg i.v. of A-131701 were required to lower blood pressure by 10 mm Hg in these dogs (pED 10 = 5.57), indicating a uroselectivity ratio of >250, superior to doxazosin, terazosin, or tamsulosin. Thus, A-131701 is selective for α 1A - and α 1D - vs. α 1B -adrenoceptors in vitro, and prostatic function vs. blood pressure effects in vivo, which may provide therapeutic advantages in the treatment of BPH.

ABT-089 [3-(2(S)-pyrrolidinylmethoxy)-2-methylpyridine] is a cholinergic channel modulator (ChCM) that selectively affects the function of neuronal nicotine acetylcholine receptor (nAChR) subtypes, enhances cognitive performance and has neuroprotective activity. Previous reports indicate that, unlike the other nicotinic receptor ligands, ABT-418 and (-)- nicotine, ABT-089 exhibits a more complex profile, having agonist, partial agonist, and inhibitory activities depending on the putative nAChR subtype with which it interacts. This study provides safety and pharmacokinetic information that clearly differentiate ABT-089 from both (-)-nicotine and ABT-418. ABT-089 has a reduced activation of ganglionic nAChRs, resulting in a reduced propensity to elicit side effects at high doses. Studies using guinea pig ileum indicate that ABT-089, in contrast to (-)- nicotine and the muscarinic agonist,methacholine, has no detectable effects on smooth muscle contractility, suggesting low potential for interference with gastrointestinal mobility. ABT-089 is orally available (33–76% in rat, dog, and monkey) and preliminary formulation data indicates that once-a-day formulation is feasible. In contrast, ABT-418 and (-)-nicotine have poor oral bioavailability in dog and monkey (

Progress in the identification of novel P1 and P2 receptor ligands has continued to lag behind the explosion in receptor cloning, especially in the P2 area. Nonetheless, a number of novel chemical entities and natural receptor ligands are continuing to advance in clinical trials or, alternatively have become important new tools to study receptor function. Compounds of note with activity at the P1 receptor family include NNC 21-0136 (A 1 agonist; preclinical; stroke); SCH 59761 (nonselective P1 agonist; preclinical; cardiovascular disorders); the A 1 antagonists, KFM-19 (BIIP-20; phase II) and MDL 102,503 development (status unknown) that may have therapeutic potential as cognition enhancers. KF 17837 and related A 2A -antagonists such as KW 6002 represent potential novel treatments for Parkinson's disease. SCH 58261 (A 2A receptor antagonist; preclinical) is a novel nonxanthine antagonist ligand. KW 3902 (phase II), FK- 453/FK 113453 (possibly discontinued) and CVT-124 (phase I) are A 1 receptor-selective xanthine-based antagonists that have potential in the treatment of renal diseases. NNC 53-0055 (preclinical) is the first of a new series of selective A 3 receptor agonists that modulate cytokine production. MRS 1067, MRS 1067, MRS 1097, MRS 1222, L-249, 313, and L-268, 605 (all preclinical) represent new A 3 -receptor antagonists. GP 3269 (preclinical) is an adenosine kinase inhibitor with potential efficacy in septic shock, stroke, and pain. ARL 67085 (phase II) is an ATP bioisostere that is an antagonist of the P 2T receptor that is the first of new generation of antithrombotic agents. Systemic ATP has reached phase II trials as a novel approach to metastasis regression. The pyrimidine nucleotide, UTP (phase II) is being examined as P2Y 2 receptor agonist for the treatment of cystic fibrosis.

A-80426 (N-[2-(benzofuran-6-yl)ethyl]-N-[(R)-(+)-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl methyl]-N-methylamine) is a novel compound with potential antidepressant activity. A-80426 inhibits synaptosomal serotonin (5HT) uptake (IC 50 = 13 nM) more potently than fluoxetine (IC 50 = 308 nM), and blocks [ 3 H]-paroxetine binding (K 1 = 3.8 nM) to 5HT uptake sites. A-80426 inhibits [ 3 H]-rauwolscine binding to α2-adrenoceptors (K 1 = 2.0 nM), blocks α2-adrenoceptors (pEC 30 = 7.4-7.5) in electrically stimulated rat atria and vas deferens, and increases electrically stimulated [ 3 H]-NE overflow from brain slices. A-80426 lacks significant activity at isolated tissue models of α 1 - or β-adrenergic sites or at M 3 muscarinic or H 1 histaminergic receptors. A-80426 has negligible radioligand binding activity at 5HT 1 and β-adrenergic receptors, but exhibits a K 1 value of 144 nM at 5HT 2 receptors. A-80426 interacts with both dopamine D 1 (K 1 = 744 nM) and D 2 (K 1 = 51.5 nM) receptors. Functionally, the compound antagonizes dopamine-induced changes in cyclic AMP formation with K 1 values of 133 nM and 185 nM at D 1 and D 2 receptors, respectively. The potent α 2 -adrenoceptor blocking activity of A-80426 in radioligand binding assays is not reflected in isolated tissue bioassays, and may thus have less functional consequence in determining the in vivo profile of the compound. Accompanying behavioral data [Giardina et al., 1995], while indicating activity in the olfactory bulbectomized rat model of antidepressant action, shows a marked reduction in the α 2 -antagonistic properties of A-80426 in other in vivo models, suggesting that the antidepressant-like activity may be caused primarily by inhibition of 5HT uptake.

A-80426 N-[2-(benzofuran-6-yl)ethyl]-N-[(R)−( + (-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl methyl]-N-methylamine) is a compound that combines in vitro selective inhibition of serotonin synaptosomal uptake and α2-adrenoceptor antagonism. In the present studies, A-80426 was evaluated in vivo for its ability to block serotonin uptake and α2-adrenoceptors. The antidepressant potential of the compound was also assessed. In rats, A-80426 significantly reduced p-chloroamphetamine (PCA)-induced hyperactivity, a measure of the in vivo blockade of serotonin uptake, after acute (ED50 = 13 μmoles/kg, po) and chronic (14 day) (ED50 = 4.1 μmoles/kg, po) dosing. At doses of 6.7 and 22 μmoles/kg, po, A-80426 was effective in this test procedure for at least 12 h following administration. Doses of 6.7 to 224 μmoles/kg, ip, of A-80426, however, failed to block hypothermia and hypoactivity produced by the α2-adrenoceptor agonist clonidine, and doses of 100 and 300 μmoles/kg, po, were required to blocked clonidine-induced mydriasis. Thus, the in vitro α2 receptor binding and blocking effects observed with A-80426 did not translate into the in vivo situation. A-80426 was able to reverse the step-down passive avoidance deficit seen in olfactory bulbectomized rats (ED70 = 7.1 μmoles/kg, po), a finding suggesting that the compound has antidepressant potential. The compound was, however, inactive in the tail suspension and forced swim tests of antidepressant activity in mice at doses up to 72 μmoles/kg, ip. In contrast, fluoxetine was active in all three paradigms. Despite its favorable in vitro profile, A-80426 is not an effective α2 blocker in vivo and is inactive in the behavioral dispair models of depression. It is unlikely that A-80426 would have antidepressant activity equivalent to existing selective serotonin reuptake inhibitors. α2 blockade as a potential approach to eliciting antidepressant activity is discussed. © 1995 Wiley-Liss, Inc.

The premise that purinergic nucleosides and nucleotides subserve roles as autocrine agents, neurotransmitters, or neuromodulators has been well established over the past 20 years. Mechanistically, adenosine, the endogenous ligand for P1 type purinoceptors, acts to modulate the release of a variety of neurotransmitters as well as modulating the effects of such agents at the postsynaptic level. P2 receptor agonists, including ATP and ADP, appear to act more like traditional neurotransmitters undergoing quantal release and producing their effects directly through G-protein linked receptors or ligand gated ion channels. There is, however, little direct evidence at this time for pathophysiologies directly attributable to purinoceptor malfunction. Nonetheless, the adenosine formed from ATP breakdown appears to play a protective role in hypoxic and ischemic situations. And adenosine A1 agonists as well as agents that act to potentiate the actions of endogenous adenosine (AICA riboside, adenosine uptake blockers, adenosine kinase inhibitors etc.) are being evaluated for use in stroke and reperfusion injury. A1 receptor agonists may also have potential as anticonvulsants and in the treatment of type II diabetes. A2a receptor ligands because of their unique co-localization with D2 receptor containing neurons in the striatopalladial pathway of the basal ganglia may have potential use in the treatment of diseases involving dopaminergic malfunction for instance, Parkinsonism and schizophrenia. Agonists therapy may, however, be limited by the non-specific actions of agonists at nontarget tissues and the tolerance typically associated with chronic agonist therapy. As a result, there is increased focus on indirect modulation of adenosine systems by either adenosine potentiators or allosteric modulators, the latter class including PD 81, 723 and the newly discovered peptide, adenoregulin. Approaches to adenosine antagonists and therapeutic agents have resulted in the identification of 8-substituted xanthines including KFM 19 and MDL 102, 234 that are currently being evaluated as cognition enhancers with potential use in Alzheimer's disease. While chemistry in the area of P2 purinoceptor has been limited, ATP itself may have potential use in the treatment of cancer and shock. Continued progress in the understanding of the physiological role of the various classes of purinoceptor has the potential to lead to novel therapeutics in the 1990s. © 1993 Wiley-Liss, Inc.

The minaprine analog SR 95639A (morpholinoethylamino-3-benzocylohepta-(5,6-c)pyridazine dihydrochloride), a putative muscarinic M1 receptor agonist, was evaluated for muscarinic activity in a number of biochemical and behavioral tests. Binding studies indicated that SR 95639A was 4-fold selective for the M1 receptor. In contrast, both carbachol and the Merck “super agonist,” L 670,207, were 50-fold selective for the M2 receptor, with Ki values of 47 μM and 100nM at the M1 receptor and 1 μM and 2nM at the M2 receptor, respectively. At concentrations up to 1 mM, SR 95639A had no effect on M1 receptor-evoked phosphatidyl inositol (Pl) hydrolysis, while carbachol and L 670,207 had EC50 values of 116±10 μM and 0.60±0.12 μM respectively. SR 95639A (100 μM) did not inhibit the Pl response elicited by carbachol. At striatal M2 receptors linked to inhibition of forskolin-mediated cyclic AMP production, SR 95639A at concentrations up to 100 μM had no agonist activity, while carbachol and L 670,207 had respective EC50 values of 540±31 nM and 2.9±0.5 nM. However, SR 95639A was an effective antagonist (K app = 3.50±0.45 μM; n = 5) of the carbachol response. In a rat radial arm maze paradigm, SR 95639A did not enhance cognitive performance and was unable to reverse deficits induced by scopolamine. The compound produced a dose-dependent increase in mouse locomotor activity and did not attenuate the effects of scopolamine on habituation, but did potentiate oxotremorineinduced hypothermia.

MK-801 was evaluated in rats for “antipunishment” and “anticonflict” activity in two procedures: (1) A conditioned emotional response (CER) test involving the suppression of lever-pressing by unaviodable shock and (2) a simple conflict test in water-deprived animals that were shocked for licking water. The effect of MK-801 in both procedures was qualitatively similar to the benzodiazepines. Lever-pressing in the CER test was increased by MK-801 at doses ranging from 50–400 μg/kg administered orally (p.o.) at either 0.5 or 2 hours prior to testing. The number of shocks received in the “thirsty rat” conflict procedure was increased by MK-801 at doses from 110–1,000 μg/kg p.o., providing the compound was given 2 or more hours before test. MK-801 was without anticonflict activity when administered 1 hour prior to study. In squirrel monkeys trained in a response-contingent conflict paradigm, a specific anticonflict effect for MK-801 (50–400 μ/kg p.o.) was not demonstrable. As assessed by observing the overt behavior of squirrel monkeys, MK-801 at doses greater than 100 μg/kg p.o. caused apparent “taming” or “tranquilization.” Chlordizepoxide and diazepam given, respectively, at doses above 1 and 2 mg/kg p.o. had a similar “taming” action. The benzodiazepines possessed a greater separation between doses producing “taming” and those causing ataxia than did MK-801. The mode of action for the antipunishment effect of MK-801 in rats is not known, but it was found that naloxone (2 or 5 mg/kg SC) antagonized the anticonflict actions of both MK-801 and chlordiazepoxide. In vitro, MK-801 was inactive (IC50 > 2 μM) with respect to competing for binding to rat brain tissue by various radioligands (diazepam, muscimol, apomorphine, spiroperidol, serotonin, LSD, WB-4101, dihydroalprenolol, QNB, and 2-chloroadenosine). An increase in 3H-diazepam binding in vitro in rat brain tissue was detected following acute, but not chronic, treatment in vivo with MK-801.

The enantiomers of the novel oxaergoline dopamine (DA) agonist, 6-ethyl-9-oxaergoline (EOE) were compared with the parent recemate for their interactions with dopamine and other monoamine receptor systems in mammalian and teleost nervous tissue. The (−)enantiomer of EOE was over 100 times more active in displacing [3H]apomorphine than the (+)isomer, and 70 times more active in displacing [3H]spiperone. The (−)isomer also exhibited greater binding affinity at serotonin-1 and -2 receptors than the (+)isomer. In contrast, however, the α1- and α2-adrenoceptor activity of the compound resided in the (+)isomer, the latter being some 32 times more active at α2 than α1 adrenoceptors. Examination of EOE in the DA-sensitive adenylate cyclase system of carp retina showed that while the (−)enantiomer was a partial agonist some 30 times less active than dopamine, the (+)enantiomer was devoid of activity in this D-1 coupled system at concentrations up to 300 μM.

The binding of the selective ligand [3H]cyclohexyladenosine (CHA) to adenosine A1 receptors was studied in brain membrane from six species; cow, rabbit, rat mouse, human, and guinea pig. Saturation analysis gave evidence for a single binding site in each species. The number of binding sites (2.6–4.7 pmol/mg protein), based on saturation analysis, was virtually identical in each species. The Kd values were, however, different; whereas rat, rabbit, and mouse A1 receptors had similar affinities (Kd=1–2 nM), the binding site in bovine tissue had three to four times greater affinity (Kd=0.59 nM). Adenosine binding sites in human and guinea pig brain had two to three times less affinity, with Kd values 3.7 and 6.6 nM, respectively, than those in rat, rabbit, and mouse brain. Examination of the binding of five agonists, the R and S diastereomers of N6-phenylisopropropyladenosine (PIA), CHA, 5′N-ethylcarboxamido adenosine (NECA), and 2-chloroadenosine, and of five xanthine antagonists, PACPX [1,3,dipropyl-8-(2-amino-4-chloro)phenylxanthine], 1,3 diethyl-8-phenylxanthine (DPX), 8-phenyltheophylline (8PT), 8-parasulfophenyl-theophylline (8PST), and theophylline, showed that across the species N6-substituted adenosine analogs showed consistent differences in rank order activity. R-PIA ≥ CHA >S-PIA, with the compounds being most active in bovine tissue and least active in guinea pig, showing an 18-fold difference. In contrast, the 2-substituted analog, 2-chloroadenosine was most active in guinea pig and human brain membranes, and least active in rat and bovine brain. The 5′-substituted analog NECA had similar activity in all species studied. PACPX was the most potent of the xanthines studied, being most active in bovine brain tissue and least active in guinea pig; the difference in activities was 393-fold. The interaction of the remainder of the xanthines studied was complex. In general, the rank order of potency was PACPX > DPX=8 phenyltheophylline > 8PST >> theophylline. However, in human and rabbit brain 8PT was more active than DPX, and in guinea pig 8PT was twofold less active than DPX. In addition, in human and guinea pig brain, 8PST had comparable activities. These differences in pharmacological profiles may be attributable to differences in the adenosine systems studied as previously noted by Murphy and Snyder [Mol. Pharmacol. 22:250–257, 1982], which may in turn reflect distinct differences in A1 receptors or the presence of different subtypes of adenosine receptor in the various species. While these interspecies studies need to be extended to both A2 receptors and to coupled, i.e., adenylate cyclase, systems, they underline the need for care in choosing the mammalian species in which structure activity relationships are generated. Some caution is necessary in the use of bovine brain tissue in development programs targeted towards therapeutic entities in the adenosine A1 antagonist area.

[3H]5′-N-Ethylcarboxamidoadenosine (NECA) labels both A1 and A2 adenosine receptors in mammalian brain tissue. In the presence of 50 nM N6-cyclopentyladenosine (CPA), however, to block selectively the A1 component of binding, [3H]NECA labels two binding components in striatal tissue. Such binding is dependent on the presence of Mg2+ ions and the removal of endogenous adenosine, using the catabolic enzyme, adenosine deaminase. The two binding components were observed in six mammalian species–-rabbit, man, rat, mouse, guinea pig, and calf–-with dissociation constants varying between 3.2 and 9.6 nM for the higher-affinity site and 54 and 232 nM for the lower-affinity site. In rat brain tissue, specific binding was reduced by the presence of 5′ guanylyimidodiphosphate Gpp(NH)p, indicating the involvement of a G-protein. Gpp(NH)p effects were attributable to a conversion of a proportion of high-affinity to low-affinity components, as determined by saturation experiments. These results, together with the observation that Gpp(NH)p shifted the inhibition curve for the agonist, 2-chloro-adenosine(2-CADO), to the right indicate that the sites labeled by [3H]NECA in the presence of 50 nM CPA represent multiple affinity states rather than multiple receptor subtypes. Pharmacological examination of the higher-affinity binding component using 2 nM [3H]NECA showed that binding was consistent with the labeling of an A2 adenosine receptor in all species. The order of activity for adenosine agonists was NECA > 2-CADO > R-phenylisopropyladenosine (R-PIA) > N6cyclohexyladenosine ≥ CPA » S-PIA. The activity ratios of the diastereomers of PIA (SIR) varied between 7.9 (mouse) and 14.5 (rat). The interaction of a series of 8-phenyl-substituted xanthines showed marked species differences with 1,3-dipropyl-8-(2-amino-4-chloro) phenylxanthine (PACPX) being the most active at 14-15 nM in rabbit and man, 3-fold less active in calf, and 24-40-fold less active in guinea pig, mouse, and rat. A similar trend was seen for 8-phenyltheophylline (8-PT), 8-para-sulfo-phenyltheophylline (8-PST), and 1,3-diethyl-8-phenylxanthine (DPX), the relative order of activity of these adenosine antagonists being PACPX > 8-PT 2 DPX 2 8-PST. Caffeine and theophylline were much less active (1C50 > 10,000 nM), while the phosphodiesterase inhibitor 3-isobutyl-1 -methyl xanthine (IBMX IC50, 2,257-4,410 nM) was 2-3 times more potent in man and calf than in the other species studied.