Ian M. Mawer

The total synthesis of myo-inositol polyphosphates

Abstract Total synthesis of the individual enantiomers of myo-inositol 4-phosphate ( 15 ), myo-inositol 1,4-bisphosphate ( 2 ) and myo-inositol 1,4,5-trisphosphate ( 1 ), together with syntheses of racemic myo-inositol 1,3,4-trisphosphate ( 4 ) and myo-inositol 2,4,5-trisphosphate ( 5 ) are reported. The syntheses feature the use of camphanic acid esters for resolution of protected inositols, and the use of tetrabenzylpyrophosphate as an efficient phosphorylating agent for polyhydroxy alcohols.

Discriminative stimulus properties of the putative dopamine D3 receptor agonist, (+)-PD 128907: role of presynaptic dopamine D2 autoreceptors.

The putative D3 receptor agonist, (+)-PD 128907, is widely used to study the functional relevance of D3 receptors in vivo. Given that non-selective D2/3/4 receptor agonists serve as effective discriminative stimuli in rats we have trained animals to discriminate (+)-PD 128907 (30 microg kg(-1), s.c.) from saline and examined the pharmacological specificity of the response. Consistent with a D3 receptor mediated response, the non-selective D2/3 receptor agonist apomorphine and the D3 preferring agonists 7-OH-DPAT and (-) quinpirole generalised to the cue whilst the D2/3 receptor antagonists haloperidol, raclopride, spiperone and (+)-butaclamol antagonised drug lever responding. In contrast, the D1 selective agonist (+/-)-SKF 81297 and D1/5 selective antagonist, R-(+)-SCH 23390 had no effect. Results also suggest that presynaptic dopamine receptors are involved. Thus the dopamine depleting agent alpha-methyl-p-tyrosine potentiated the effects of a submaximal dose of (+)-PD 128907 whereas amphetamine failed to generalise per se and blocked (+)-PD 128907 lever selection. However, studies using subtype selective antagonists argue against a role for the D3 receptor. Thus the 10-fold selective D2 receptor antagonist L-741,626 blocked the (+)-PD 128907 discriminative stimulus whereas L-745,829 and GR 103,691, antagonists > 40 and > 100-fold selective for D3 receptors, failed to modify the response. These results suggest that presynaptic D2 receptors mediate the discriminative stimulus properties of (+)-PD 128907 and highlight the lack of selectivity of (+)-PD 128907 for D3 receptors in vivo.

Amino acid bioisosteres: design of 2-quinolone derivatives as glycine-site N-methyl-D-aspartate receptor antagonists

Abstract 3-Substituted-2-quinoloners ( 6–8 ) have been identified as glycine-site N-methyl-D-aspartate receptor antagonists. It is proposed that the α-phenyl lactam unit in the potent 4-hydroxy-3-phenyl derivatives ( 7d and 8b , L-701,315) may act as a glycine bioisostere in receptor recognition.

The total synthesis of myo-inositol phosphates via myo-inositol orthoformate

Novel selective alkylations of myo-inositol orthoformate (4) have been used to prepare a series of protected myo-inositol derivatives, (5a–e), (7), (10), (12), and (16). These intermediates have been used in efficient total syntheses of myo-inositol 2-phosphate, (9); myo-inositol 4-phosphate, (6); myo-inositol 1,3-bisphosphate, (18); and myo-inositol 1,3,4,5-tetrakisphosphate (14). This report represents the first total synthesis of the important natural metabolites (14) and (18) and significantly improved methods of preparation of (6) and (9).

Tetramic acids as novel glycine site antagonists

Abstract Tetramic acids ( 9 ) have been designed as novel glycine site N-methyl-D-aspartate receptor antagonists.

Synthesis of myo-inositol 1-phosphate and 4-phosphate, and of their individual enantiomers

New methodology is described which allows the synthesis of myo-inositol 1-phosphate completely free of contamination by the 2-isomer, and novel resolution procedures have been developed for the preparation of the enantiomers of myo-inositol 1- and 4-phosphates.

Synthesis and SAR of diiodotyrosine-derived glycine-site N-methyl-D-aspartate receptor ligands

Abstract A series of analogues of the novel diiodotyrosine derived NMDA glycine-site ligand (R)-4 was prepared in which the aryl substitution, chain length and amino acid groups were varied. The key structural features for binding are the α-amino acid function, having the (R) absolute stereochemistry, the 3,5-diiodo substituted aromatic ring and a lipophilic group attached at the phenolic oxygen of the tyrosine moiety.