Neil Roy Curtis

Orally Efficacious NR2B-Selective NMDA Receptor Antagonists

A novel series of benzamidines was synthesized and shown to exhibit NR2B-subtype selective NMDA antagonist activity. Compound 31 is orally active in a carrageenan-induced rat hyperalgesia model of pain and shows no motor coordination side effects.

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.

Synthesis and sar of 2- and 3-substituted 7-azaindoles as potential dopamine D4 ligands.

7-azaindole compounds bearing a cyclic amine moiety linked by a one or two carbon chain attached at the 2- or 3-position were synthesised and evaluated as potential dopamine D4 ligands. Highest affinity and selectivity for the D4 receptor resided in the 3-aminomethyl-7-azaindole series.

Novel N1-(benzyl)cinnamamidine derived NR2B subtype-selective NMDA receptor antagonists

Novel (E)-N(1)-(benzyl)cinnamamidines were prepared and evaluated as NR2B subtype NMDA receptor ligands. Excellent affinity was achieved by appropriate substitution of either phenyl ring. The 2-methoxybenzyl compound 1h had approximately 1,000-fold lower IC(50) in NR2B than NR2A-containing cells. Replacement of the styryl unit by 2-naphthyl was well tolerated.

Studies towards the synthesis of obtusenyne : a claisen rearrangement approach to unsaturated nine-membered lactones

Abstract An advanced intermediate for the synthesis of the Laurencia oxonane natural product obtusenyne 1 . namely the unsaturated nine-membered lactone 3 , was efficiently prepared in seven steps from ( E )-3-hexenoic acid 7. The key transformation was the Claisen rearrangement of the vinyl ketene acetal 4 , which represents novel methodology for the preparation of such unsaturated nine-membered lactones.

Studies towards the synthesis of obtusenyne. Synthesis of the hexahydrooxonin nucleus

Abstract The advanced intermediate (the 2,3,4,7,8,9-hexahydrooxonin)3 for the synthesis of the Laurencia oxonane natural product, obtusenyne1 was prepared in 8 steps from the previously reported lactone4. The key transformations were the stereoselective enolate hydroxylation of the lactone4 and a hydroxyl-directed intramolecular hydrosilation of the enol ether12.

Synthetic methodology for the preparation of trans- and cis-2,9-disubstituted oxonanes

Abstract Methylenation of the racemic lactone (5), followed by stereoselective hydroboration, gave predominantly the trans-2,9-disubstituted oxonane (7) which was converted into the carbon skeleton (1) of obtusenyne (2). Epimerisation of the trans-aldehyde (18) gave the cis-compound (19). Relative stereochemistry was established by the asymmetric synthesis of trans-(2R),(9R)-dimethyloxonane (13) and meso cis-2,9-dimethyloxonane (17).

An intramolecular hydrosilation approach to hexahydrooxonins related to obtusenyne. Effect of catalyst and conditions on stereoselectivity

Abstract The intramolecular hydrosilation of the α-dialkylsilyloxy enol ethers 3 and 5 followed by oxidative work-up resulted in the diastereoselective synthesis of either the hexahydrooxonin diol 7 or 8 according to the catalyst and conditions employed.

SYNTHESIS OF (-)-GLOEOSPORONE

Abstract The homochiral lactone ( 5 ) and the oxazolidinone ( 9 ), together with the phosphoniumsalt ( 15 ), serve as key building blocks for the enantioselective synthesis of the ( Z )-bis(silyloxy) ester ( 17 ), whose photochemical conversion into the ( E )-isomer ( 18 ) constitutes a formal synthesis of the antifungal macrocyclic lactone (−)-gloeosporone ( 2 ). The building blocks ( 5 ), ( 9 ), ( 15 ), and ( 17 ) are used to construct the enantiomerically pure ester ( 18 ) thus constituting a formal synthesis of (−)-gloeosporone ( 2 ).

CEP-1347 increases ChAT activity in culture and promotes cholinergic neurone survival following fimbria-fornix lesion.

Recent evidence suggests that the activation of the Jun N-terminal kinase (JNK) signal transduction pathway may be important in neuronal responses to stresses such as trophic factor deprivation. Preventing the activation of JNK and expression of c-Jun may, therefore, be neuroprotective. Here, we report that the small molecule CEP-1347, which has been shown to inhibit the JNK signalling pathway, promotes cholinergic activity in cultured embryonic septal neurones. In vivo, we have shown that CEP-1347, administered either by sub-cutaneous (s.c.) injection or by continuous infusion, is partially neuroprotective, for cholinergic neurones in the medial septum, following fimbria-fornix transection. These data suggest that small molecules such as CEP-1347 may have beneficial effects in treating neurodegenerative diseases.