John Richard Harris

(+)-2-Methyl-4-carboxyphenylglycine (LY367385) selectively antagonises metabotropic glutamate mGluR1 receptors

Abstract The synthesis of three novel 4-carboxyphenylglycine derivatives is described. 2-Methyl substituents increase the antagonist potency compared to (S)-4CPG at mGluR1 receptors. Resolution of compound 1 showed that the activity resided in the (+)-isomer LY367385.

Metabotropic glutamate autoreceptors of the mGlu5 subtype positively modulate neuronal glutamate release in the rat forebrain in vitro

In the present study we have examined the role of presynaptic group I metabotropic glutamate (mGlu) receptors in the control of neuronal glutamate release using rat forebrain slices pre-loaded with [(3)H]D-aspartate. We have also addressed the question of which group I mGlu receptor subtype, mGlu(1) or mGlu(5), mediates the facilitatory response observed by the use of a range of established and some more novel agonists and antagonists showing selectivity for these receptors. The electrically-stimulated release of pre-loaded [(3)H]D-aspartate from rat forebrain slices was markedly potentiated by the potent group I mGlu receptor agonist, L-quisqualic acid (L-QUIS), in a concentration-dependent manner (EC(50) 17.31 microM). This response was inhibited by the mGlu receptor antagonists (S)-MCPG (100 microM) and (RS)-MTPG (100 microM) but not by the AMPA-type ionotropic glutamate receptor antagonist, NBQX (100 microM). The selective group I mGlu receptor agonist (S)-3, 5-dihydroxyphenylglycine ((S)-DHPG) also enhanced electrically-stimulated efflux of label, although responses diminished with high (10-100 microM) concentrations of the agonist. Maximum responses were fully restored when (S)-DHPG (10 microM) was applied in the presence of the proposed mGlu(5) receptor desensitization inhibitor, cyclothiazide (10 microM). The positive modulatory response to (S)-DHPG (1 microM) was powerfully inhibited by (S)-MCPG (IC(50) 0.08 microM) but was resistant to the mGlu(1) receptor antagonists, (RS)-AIDA (1-500 microM), CPCCOEt (0.1-100 microM) and (+)-2-methyl-4-carboxyphenylglycine (LY367385) (0.1-10 microM). The recently developed, selective mGlu(5) receptor agonist (RS)-2-chloro-5-hydroxyphenylglycine ((RS)-CHPG) enhanced electrically-stimulated [(3)H]D-aspartate efflux from rat forebrain slices with a similar concentration-response profile to that of (S)-DHPG. Responses to this receptor subtype-selective agonist were also blocked by (S)-MCPG (IC(50) 1.13 microM) but were unaffected by (RS)-AIDA (500 microM), CPCCOEt (100 microM) or LY367385 (10 microM). These results indicate that the positive modulation of neuronal glutamate release seen in the rat forebrain in the presence of group I mGlu receptor agonists is mediated by presynaptically located mGlu(5) glutamate autoreceptors. The pharmacological profile of these receptors appears to be distinct from that of postsynaptic mGlu receptors. Novel antagonists acting at these presynaptic receptors may provide new drugs for the experimental therapy of a range of acute or chronic neurodegenerative disorders.

Neuroprotective Actions of Novel and Potent Ligands of Group I and Group II Metabotropic Glutamate Receptors

ABSTRACT: The role of group I metabotropic glutamate (mGlu) receptors in neurodegeneration is controversial because of the contradictory effects of mGlu1/5 agonists in in vitro models of neuronal cell death. In this study, novel and selective antagonists of mGlu1 and mGlu5: LY367385 and LY367366 were found to show consistent neuroprotective effects against N‐methyl‐d‐aspartate (NMDA)‐induced excitotoxicity in vitro and in vivo. Furthermore, intraventricular administration of LY367385 reduced hippocampal cell death in gerbils subjected to transient global ischemia.

Inhibition of group I metabotropic glutamate receptor responses in vivo in rats by a new generation of carboxyphenylglycine-like amino acid antagonists

A series of novel group I metabotropic glutamate receptor (mGlu) antagonists have been designed on the basis of the 4-carboxyphenylglycine pharmacophore. The compounds are either mGlu1 receptor selective or equipotent for both mGlu1 and mGlu5 receptors and have IC(50) values ranging from 1 to 30 microM determined by phosphoinositide hydrolysis (PI) assay in vitro. All the compounds produced dose-dependent inhibition of group I mGlu receptor agonist (RS)-3,5-dihydroxyphenylglycine (DHPG)-induced limbic seizure responses in mice with ED(50) values ranging from 9 nmol for LY393053 to 138 nmol for LY339840 after intracerebroventricular injection and were more potent than the mGlu1 receptor antagonist 1-aminoindan-1,5-dicarboxylic acid (ED(50)=477 nmol). Further antagonist actions were also demonstrated in a model of (RS)-DHPG-induced PI hydrolysis in vivo such that LY367385 and the active cis isomer of LY393053 produced dose-dependent inhibition of PI responses in both cerebellum and hippocampus. Cis LY393053 also inhibited hippocampal PI responses when administered intraperitoneally at a dose of 30 mg/kg. These compounds define a new series of group I mGlu receptor antagonists which may serve as useful experimental tools.

Endogenous sulphur-containing amino acids : potent agonists at presynaptic metabotropic glutamate autoreceptors in the rat central nervous system

We have recently demonstrated that presynaptically located metabotropic glutamate (mGlu) autoreceptors regulate synaptic glutamate release both in vitro and in vivo. We now report a positive modulatory action of the sulphur‐containing amino acids (SCAAs), L‐cysteic acid (CA) and L‐cysteine sulphinic acid (CSA), at presynaptic group I mGlu receptors, specifically of the mGlu5 subtype, acting to enhance synaptic glutamate release from the rat forebrain in vitro. Neuronal glutamate release was monitored using electrically‐evoked efflux of preloaded [3H]‐D‐aspartate from rat forebrain hemisections. Both CA (3u2003–u2003100u2003μM) and CSA (1u2003–u2003100u2003μM), in addition to the selective group I mGlu receptor agonist, (S)‐3,5‐dihydroxyphenylglycine ((S)‐DHPG), concentration‐dependently enhanced electrically‐stimulated efflux of [3H]‐D‐aspartate from the rat forebrain slices. Basal efflux of label remained unchanged. The inhibitory activity of the broad spectrum mGlu receptor antagonist, (±)‐α‐methyl‐4‐carboxyphenylglycine ((±)‐MCPG; 200u2003μM), coupled with the inactivity of the selective mGlu1 receptor antagonists, (R,S)‐1‐aminoindan‐1,5‐dicarboxylic acid ((R,S)‐AIDA; 100u2003–u2003500u2003μM) and the more potent (+)‐2‐methyl‐4‐carboxyphenylglycine (LY367385; 10u2003μM) against these responses, indicates an action of the SCAAs at the mGlu5 receptor subtype. This proposal is supported by the potent inhibition of these responses by the selective, non‐competitive mGlu5 receptor antagonist, 2‐methyl‐6‐(phenylethynyl)pyridine (MPEP; 10u2003μM). The observed enhancement of the responses to high concentrations of CA by the selective mGlu5 receptor desensitization inhibitor, cyclothiazide (CYZ; 10u2003μM), is also consistent with this concept. Administration of the agonists in the presence of bovine serum albumin (BSA; 5u2003–u200315u2003mgu2003ml−1) markedly attenuated the positive modulatory responses observed, strongly supporting a role for arachidonic acid in the expression of these mGlu5 receptor‐mediated responses. The regulatory actions of SCAAs on synaptic glutamate release demonstrated in the present study may provide a physiological function for these putative neurotransmitter amino acids in the mammalian brain. These central actions of the SCAAs may have wide‐ranging implications for a range of neurological and neuropsychiatric disease states and their treatment.

New multi-bridged cryptands: Polyazamacrocyclic schiff bases formed in a tetrapode capping reaction

Abstract Multi-bridged cryptands were formed in one step by condensation of two moles of a tetraaldehyde with four moles of a triamine. This is the first example of a tetrapode capping reaction.

Syntheses of 7-Carboxyindolylglycines Utilising Glycine Cation Equivalents

Abstract Abstract: The synthesis of two 7-carboxyindolylglycines is described as putative metabotropic glutamate receptor (mGluR) antagonists, employing glycine cation equivalents in the key steps.

A Convenient Synthesis of Some 1,4-Disubstituted 7-Oxabicyclo[2.2.1]heptanes

Abstract An efficient synthesis of a 1,4-disubstituted 7-oxabicyclo[2.2.1]heptane intermediate and its subsequent conversion to a potential PAF antagonist is described.

Conversion of Agroclavine to Lysergol

Abstract The conversion of agroclavine (1) to lysergol (4) has been achieved in three steps utilising the dehydration of setoclavine (2) to lysergene (3).