Brian John Williams

Multiple tachykinin binding sites in peripheral tissues and in brain

Tachykinin binding sites in guinea pig urinary bladder (GPUB), rat salivary gland (RSG), hamster urinary bladder (HUB), rat vas deferens (RVD) and rat cerebral cortex (RCC) were compared using 125I-Bolton Hunter conjugates of substance P (125I-BHSP), eledoisin (125I-BHE) and neurokinin A (125I-BHNKA). In typical SP-P tissues (GPUB, RSG) and in RCC, SP was the most potent displacer of 125I-BHSP and [Glp6,D-Pro9]-SP(6-11) was 90 times less active than [Glp6,L-Pro9]-SP(6-11) while SP methyl ester (SPOMe) was 5-10 times more active than the Bolton Hunter conjugate of SPOMe (I-BHSPOMe). On the other hand, in typical SP-E tissues (HUB, RVD), neurokinin A was most potent in displacing 125I-BHE and [Glp6,D-Pro9]-SP(6-11) was over 300 times more active than [Glp6,L-Pro9]-SP(6-11) while SPOMe was 160 times less active than I-BHSPOMe. In rat cerebral cortex, the rank order of potency of tachykinins and related analogues in displacing 125I-BHE was distinct from that of peripheral SP-E sites, with neurokinin B being the most potent displacer, and SPOMe was over 1,000 times more active than I-BHSPOMe; 125I-BHE binding sites in CNS may represent a third category of tachykinin receptor, designated SP-N.

Piperidine-ether based hNK1 antagonists 1: Determination of the relative and absolute stereochemical requirements

Abstract 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.

Pharmacological specificity of novel, synthetic, cyclic peptides as antagonists at tachykinin receptors

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 cyclc(GlnTrpPhe(R)Gly[ANC‐2]LeuMet) (L‐659,837) and cyclo(GlnTrpPheGlyLeuMet) (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.

The anticonvulsant and behavioural profile of L‐687,414, a partial agonist acting at the glycine modulatory site on the N‐methyl‐D‐aspartate (NMDA) receptor complex

1 The anticonvulsant and behavioural effects of the glycine/NMDA receptor partial agonist, L‐687,414 (R(+)‐cis‐β‐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 15min 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., 30min 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 μg 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.

Gem-disubstituted amino-ether based substance p antagonists

Abstract 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.

Acyclic NK-1 antagonists: 2-benzhydryl-2-aminoethyl ethers

Abstract 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.

Routes to 4-substituted analogues of the glycine/NMDA antagonist HA-996. Enantioselective synthesis of (3R,4R) 3-amino-1-hydroxy-4-methyl-2-pyrrolidinone (L-687, 414).

Abstract 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).

Piperidine-ether based hNK1 antagonists 2: Investigation of the effect of N-substitution

Abstract 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.

Derivatives of 1-hydroxy-3-aminopyrrolidin-2-one (HA-966). Partial agonists at the glycine site of the NMDA receptor

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.

3-benzyloxy-2-phenylpiperidine NK1 antagonists: The influence of alpha methyl substitution

Abstract 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