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Background: Codeine is frequently added to paracetamol to treat post-operative dento-alveolar pain; studies have shown effectiveness in relief of post-operative pain at high doses but at the expense of central nervous and gastrointestinal side effects. There has been no trial to compare the efficacy and safety of paracetamol 1000mg with paracetamol 1000mg combined with codeine 30mg. Method. A randomized, single centre, double-blind prospective parallel group trial was performed to compare paracetamol 1000mg with paracetamol 1000mg with codeine 30mg for the relief of pain following surgical removal of impacted third molars, and analysed on an intention-to-treat (ITT) basis. Eighty-two patients were assigned randomly to receive either drug for a maximum of three doses. Patients recorded their pain intensity one hour after surgery and hourly thereafter for 12 hours. Results: The average increase in pain intensity over 12 hours was significantly less in patients receiving paracetamol plus codeine than in those receiving paracetamol alone (p=0.03) -1.81cm/h compared with 0.45cm/h - a difference of 1.13cm/h (95 per cent Cl: 0.18 to 2.08). Of the patients who received the paracetamol codeine combination, 62 per cent used escape medication compared with 75 per cent of those on paracetamol alone (p=0.20). There was no significant difference between the two groups in the proportion of patients experiencing adverse events (P=0.5). Conclusion: A combination of 1000mg paracetamol and 30mg codeine was significantly more effective in controlling pain for 12 hours following third molar removal, with no significant difference of side effects during the 12 hour period studied.

The putative neurotrophic effects of the immunophilin ligand GPI-1046 were evaluated in established experimental systems of neuron survival and axon growth in vitro and in vivo. GPI-1046 marginally increased neurite outgrowth of chick dorsal root ganglia in culture under conditions where a very robust effect of nerve growth factor was seen. GPI-1046 failed to protect dopaminergic neurons from 1-methyl-4-phenylpyridinium in culture or to protect cultured cortical neurons from experimentally induced apoptosis in vitro. In adult rats in vivo, daily administration of GPI-1046 (10 mg/kg, s.c.) for three days enhanced the maximal regeneration distance of both motor and large myelinated sensory axons measured using an electrophysiological assay. However, detailed morphometric analysis of these animals failed to provide evidence for an increase in axon numbers in GPI-1046-treated animals. The ability of GPI-1046 to promote the recovery of dopaminergic function following unilateral 6-hydroxydopamine lesions of the substantia nigra was also tested in rats. In the first study, the duration of amphetamine (3 mg/kg, s.c.)-induced circling, but not the maximal number of rotations, was significantly reduced in animals treated with GPI-1046 for five days (10 mg/kg/day). In a second study, testing the effects of delayed GPI-1046 administration, chronic treatment with GPI-1046 (10 mg/kg/day) for two weeks, beginning one month after surgery, did not alter circling responses. Morphometric analysis failed to reveal any changes in either the density of tyrosine hyroxylase-positive fibres in dopaminergic target areas or in cell numbers in the substantia nigra in both experiments. Thus, while GPI-1046 produced marginal effects on neurite outgrowth in dorsal root ganglia cultures and on functional paramaters of nerve regeneration in vivo, we failed to obtain evidence in support of the notion of a general neuroprotective effect of the compound or for an effect on morphologic nerve regeneration in vivo.

In vitro metabolism studies on a series of 3,5-bis(trifluoromethyl)benzyl ethers have identified 3,5-bis(trifluoromethyl)benzoic acid as a significant metabolite possibly arising via oxidation of the benzylic position. A methyl group was introduced in an effort to suppress this route of metabolism. One diastereoisomer displayed an increase in affinity and a marked improvement in duration of action. In vitro metabolism studies on a series of 3,5-bis(trifluoromethyl)benzyl ethers have identified 3,5-bis(trifluoromethyl)benzoic acid as a significant metabolite possibly arising via oxidation at the benzylic position. A methyl group was introduced in an effort to suppress this route of metabolism. One diastereoisomer displayed an increase in affinity and a marked improvement in duration of action

The effect of nitrogen substitution on the binding affinity of the piperidine-ether substance P antagonist L-733,060 for the hNK 1 receptor and L-type Ca 2+ channel is discussed.

The synthesis of a new series of piperidine-based ethers is described and the relative and absolute stereochemical requirements necessary for high affinity binding to the hNK1 receptor established. The synthesis of the corresponding pyrrolidine derivative is also presented.

1. The anticonvulsant and behavioural effects of the glycine/NMDA receptor partial agonist, L-687,414 (R(+)-cis-beta-methyl-3-amino-1-hydroxypyrrolid-2-one) have been investigated in rodents. 2. L-687,414 dose-dependently antagonized seizures induced by N-methyl-D,L- aspartic acid (NMDLA, ED50 = 19.7 mg kg-1), pentylenetetrazol (PTZ, ED50 = 13.0 mg kg-1) and electroshock (ED50 = 26.1 mg kg-1) when given intravenously 15 min before test, in male Swiss Webster mice but was most potent against audiogenic seizures induced by a 120 dB bell in DBA/2 mice (ED50 = 5.1 mg kg-1, i.p., 30 min before test). 3. L-687,414 also induced impairments of performance in a rotarod test in both Swiss Webster and DBA/2 mice and the ratio [rotarod MED:anticonvulsant ED50] varied between 0.9 and 5, depending on the convulsant used. 4. Similar behaviours to those seen after administration of the non-competitive NMDA receptor antagonist, MK-801 (head weaving, body rolling, hyperlocomotion) were seen in the mouse after giving L-687,414, although the peak effect occurred at a dose (100 mg kg-1) which was 5-20 times the anticonvulsant ED50S, depending on the convulsant used. Unlike MK-801, however, doses of L-687,414 that were behaviourally stimulant did not increase dopamine turnover in the nucleus accumbens. 5. Consistent with the interaction of L-687,414 with the glycine/NMDA receptor, the anticonvulsant, ataxic and motor stimulant effects of the compound were significantly attenuated by the glycine/NMDA receptor agonist, D-serine (10-100 micrograms per mouse, i.c.v.). 6. The results show that L-687,414 is a potent, orally active anticonvulsant with a more benign pharmacological profile than antagonists acting at the ion channel of the NMDA receptor complex. The compound is a useful tool with which to probe the functional role of the glycine co-agonist site in vivo.

An exploration of benzhydryl replacements is described. Whilst bridged and fused polynuclear aromatic systems both incur a reduction in affinity it was possible to replace the benzhydryl by a single phenyl ring with only a modest reduction in affinity. In contrast to the analogous diphenylalanyl ethers the binding was also shown to be stereoselective.

A series of 2-aminoethyl ethers based on diphenylalaninol have been shown to have significant affinity for the human NK 1 receptor and reduced affinity at the L-type Ca ++ channel compared with quinuclidines related to CP 96,345.

The in vitro activies of 4-substituted and bicyclic analogues of the glycine-site NMDA partial agonist HA-966 (1) reveal strict structure-activity requirements reflecting subtle conformational and steric requirements for receptor binding. The most active compounds have cis-4-methyl or hydroxyl substituents and it is suggested that the in vivo anticonvulsant activity and good brain penetration of the optimal compound (+) 2 (L-687,414) result from the high fraction of (+) 2 which is not ionised at physiological pH.

Twenty homodetic cyclic peptides based on the C-terminal sequence of substance P were prepared (Table I) by a combination of solid-phase techniques and cyclizations using azide coupling procedures. Incorporation of dipeptide mimics based on substituted gamma-lactams were used in some cases to restrict their conformational mobility. Five of these cyclic peptides were shown to have high tachykinin antagonist activity (pA2 > 6) at NK-2 receptors (rat vas deferens). The two most potent of this series, XVII, cyclo(Gln-Trp-Phe-Gly-Leu-Met) (pA2 = 8.1), and I cyclo(Gln-Trp-Phe(R)Gly[ANC-2]Leu-Met) (pA2 = 6.7), were selective for NK-2 receptors compared with the other tachykinin receptors (Table II).

Aims Clinical concern had arisen at our centre that there was delayed tracing of some paediatric contacts of tuberculosis (TB) due to high clinical workload and patient non-attendance. We therefore aimed to evaluate the size of the problem and instigate interventions to improve the service. Methods Figure 1 shows the pathway for tracing child contacts and highlights potential points of delay. We identified 23 child contacts of confirmed TB and audited their clinical notes. We determined the number of children who were traced on target, and the median times taken for children to move through the pathway. On the basis of this we implemented new guidelines with stringent time frames for the highest risk children and reaudited the service, evaluating a further 59 cases. Results Table 2 shows the number of children who moved through the pathway on target, broken down by risk. The table demonstrates a non-significant improvement in children meeting these targets particularly in the high and medium risk groups. Patients not attending appointments (DNAs) affected 11 of 23 cases in the initial audit and 13 of 59 cases in the re-audit. Comparing audits there is no overall difference in “delay 1” (median 21 vs 22 days respectively, p = 0.71). However, after the intervention, there is a non-significant improvement in “delay 2”, children being seen more quickly by the paediatric consultant if necessary (median 22 vs 17 days, p = 0.3). Conclusions There are no national guidelines towards timings. The interventions instigated in this service improvement project have led to a trend towards meeting stringent targets, particularly in high and medium risk children. However, reliably meeting such targets is difficult particularly when DNAs present such a significant problem. A standard letter has been developed to send to parents of high-risk non-attenders warning that referrals to social care will be made if not brought to hospital. Further work is needed to continue to improve the service offered.

An exploration of benzhydryl replacements is described. Whilst bridged and fused polynuclear aromatic systems both incur a reduction in affinity it was possible to replace the benzhydryl by a single phenyl ring with only a modest reduction in affinity. In contrast to the analogous diphenylalanyl ethers the binding was also shown to be stereoselective.

Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d ) we describe Astex's approach to screening fragments against Hsp90 and the subsequent optimization of two hits into leads with inhibitory activities in the low nanomolar range. This paper describes the structure guided optimization of the 2,4-dihydroxybenzamide lead molecule 1 and details some of the drug discovery strategies employed in the identification of AT13387 (35), which has progressed through preclinical development and is currently being tested in man.

Glycine anion (4) and glycine cation (8) synthons are used in efficient syntheses of 4-substituted analogues of HA-966 (1). A stereospecific route to cis derivatives involves hydrogenation of enamines such as 16. Introduction of a chiral auxiliary leads to an enantioselective synthesis of 2a (L-687, 414).

1. Tachykinin-stimulated inositol phospholipid hydrolysis was examined in slices of rat parotid gland, hamster urinary bladder and guinea-pig ileum longitudinal muscle. 2. In the presence of lithium, substance P and other naturally-occurring and synthetic tachykinins induced large, dose-dependent increases in [3H]-inositol monophosphate accumulation. 3. In slices of rat parotid gland, [pGlu6,L-Pro9]SP(6-11) was considerably more potent in stimulating inositol phospholipid hydrolysis than [pGlu6,D-Pro9]SP(6-11). 4. In contrast, in slices of hamster urinary bladder, [pGlu6,D-Pro9]SP(6-11) exhibited greater potency in evoking inositol phospholipid breakdown than [pGlu6,L-Pro9]SP(6-11). 5. The differential selectivity of these C-terminal fragments of substance P suggests that they may be useful tools for distinguishing between NK1 and NK2 receptors. 6. L-659,837 and L-659,874 antagonized eledoisin-stimulated inositol phospholipid hydrolysis in slices of hamster urinary bladder. Neither compound significantly reduced substance-P evoked inositol phospholipid breakdown in slices of rat parotid gland, or senktide-induced inositol phospholipid hydrolysis in slices of guinea-pig ileum. 7. L-659,837 and L-659,874 had no effect on the atropine-sensitive, carbachol-stimulated inositol phospholipid hydrolysis in slices of rat parotid gland. 8. These data further support the notion that L-659,837 and L-659,874 are potent and selective NK2 receptor antagonists.

A new class of potent NK3R antagonists based on the N',2-diphenylquinoline-4-carbohydrazide core is described. In an ex vivo assay in gerbil, the lead compound 2g occupies receptors within the CNS following oral dosing (Occ(90) 30 mg/kg po; plasma Occ(90) 0.95 microM) and has good selectivity and promising PK properties.

The 3,4-fused sulfamides, sulfonamides and sulfone have been identified as highly potent γ-secretase inhibitors. Evaluation of the SAR of substitution within these series has allowed the identification of a range of compounds which significantly reduce brain Aβ in transgenic mouse models and thus have potential as possible treatments for Alzheimer’s disease.

A series of novel spiroether-based neurokinin-1 (NK 1 ) antagonists is described. The effect of modifications to the spiroether ring and aromatic substituents are discussed, leading to the identification of compounds with high affinity and excellent CNS penetration.

A series of novel spiroketal-based NK(1) antagonists is described. The effect of modifications to the spiroether ring and aromatic substituents are discussed, leading to the identification of compounds with high affinity and excellent CNS penetration.

1. The interaction at tachykinin receptors of a series of novel cyclic hexapeptides has been examined by use of radioligand binding assays (NK1 and NK3 sites in rat cortex, NK2 sites in hamster urinary bladder) and functional pharmacological assays (guinea-pig ileum, rat vas deferens and rat portal vein for NK1, NK2 and NK3 receptors, respectively). 2. The compounds cyclo(GlnTrpPhe(R)Gly[ANC-2]LeuMet) (L-659,837) and cyclo(GlnTrpPheGly-LeuMet) (L-659,877) were powerful and selective displacers of NK2 binding (pIC50 6.9 and 8.0, respectively), and were competitive antagonists of responses to stimulation of NK2 receptors in rat vas deferens (pKB for antagonism of responses to eledoisin 6.7 and 8.1, respectively). Responses in the NK1 and NK3 pharmacological assays were blocked only weakly, if at all. 3. In the longitudinal muscle of the small intestine of the rat, responses to stimulation of the putative NK2 receptor by eledoisin, neurokinin A or neurokinin B were antagonized by both cyclo(GlnTrpPhe(R)-Gly[ANC-2]LeuMet) and cyclo (GlnTrpPheGlyLeuMet) in a manner consistent with the presence in this tissue of a uniform population of receptors, indistinguishable from the NK2 receptor of the rat vas deferens. 4. The compounds cyclo(GlnTrpPheGlyLeuMet) and the lactam-containing analogue are among the most selective antagonists for the NK2 receptor that have been described; their availability should be of value in the characterization of the receptors mediating responses to tachykinins, and in elucidating the physiological functions of the tachykinin receptors.

Derivatives of the nonselective excitatory amino acid antagonist kynurenic acid (4-oxo-1,4-dihydroquinoline-2-carboxylic acid, 1) have been synthesized and evaluated for in vitro antagonist activity at the excitatory amino acid receptors sensitive to N-methyl-D-aspartic acid (NMDA), quisqualic acid (QUIS or AMPA), and kainic acid (KA). Introduction of substituents at the 5-, 7-, and 5,7-positions resulted in analogues having selective NMDA antagonist action, as a result of blockade of the glycine modulatory (or coagonist) site on the NMDA receptor. Regression analysis suggested a requirement for optimally sized, hydrophobic 5- and 7-substituents, with bulk tolerance being greater at the 5-position. Optimization led to the 5-iodo-7-chloro derivative (53), which is the most potent and selective glycine/NMDA antagonist to date (IC50 vs [3H]glycine binding, 32 nM; IC50's for other excitatory amino acid receptor sites, greater than 100 microM). Substitution of 1 at the 6-position resulted in compounds having selective non-NMDA antagonism and 8-substituted compounds were inactive at all receptors. The retention of glycine/NMDA antagonist activity in heterocyclic ring modified analogues, such as the oxanilide 69 and the 2-carboxybenzimidazole 70, suggests that the 4-oxo tautomer of 1 and its derivatives is required for activity. Structurally related quinoxaline-2,3-diones are also glycine/NMDA antagonists, but are not selective and are less potent than the 1 derivatives, and additionally show different structure-activity requirements for aromatic ring substitution. On the basis of these results, a model accounting for glycine receptor binding of the 1 derived antagonists is proposed, comprising (a) size-limited, hydrophobic binding of the benzene ring, (b) hydrogen-bond acceptance by the 4-oxo group, (c) hydrogen-bond donation by the 1-amino group, and (d) a Coulombic attraction of the 2-carboxylate. The model can also account for the binding of quinoxaline-2,3-diones, quinoxalic acids, and 2-carboxybenzimidazoles.

4-Fluorophenylglycine 1 is resolved to 99.0% e.e. and 65% overall yield via its methyl ester 2 using a crystallisation induced resolution.

The design and syntheses of new series of gem -disubstituted pyrrolidine and piperidine derivatives (eg. 2 and 3 ) is described. The design and syntheses of new series of gem -disubstituted pyrrolidine and piperidine derivatives (eg. 2 and 3 ) is described.

Tachykinins are a family of peptides that share the carboxyl-terminal sequence Phe-X-Gly-Leu-Met-NH2 and that cause contraction of various smooth muscle systems. Substance P (Chang and Leeman, 1970) and the newly discovered neurokinin A (Maggio et al., 1983; Minamino et al., 1984a; Kimura et al., 1983) and neurokinin B* (Kimura et al., 1983; Kangawa et al., 1983) are mammalian tachykinins. Several nonmammalian tachykinins have been isolated, which include eledoisin, physalaemin, kassinin, and phyllomedusin (for a review, see Erspamer and Melchiorri, 1983). The amino acid sequences of these peptides are shown in Fig. 1.