Chunrong Ma

The Reinforcing Properties of Alcohol are Mediated by GABA A1 Receptors in the Ventral Pallidum

It has been hypothesized that alcohol addiction is mediated, at least in part, by specific γ-aminobutyric acidA (GABAA) receptors within the ventral pallidum (VP). Among the potential GABAA receptor isoforms regulating alcohol-seeking behaviors within the VP, the GABAA α1 receptor subtype (GABAA1) appears pre-eminent. In the present study, we developed β-carboline-3-carboxylate-t-butyl ester (βCCt), a mixed agonist–antagonist benzodiazepine (BDZ) site ligand, with binding selectivity at the A1 receptor to explore the functional role of VPA1 receptors in the euphoric properties of alcohol. The in vivo actions of βCCt were then determined following microinfusion into the VP, a novel alcohol reward substrate that primarily expresses the A1 receptor. In two selectively bred rodent models of chronic alcohol drinking (HAD-1, P rats), bilateral microinfusion of βCCt (0.5–40 μg) produced marked reductions in alcohol-reinforced behaviors. Further, VP infusions of βCCt exhibited both neuroanatomical and reinforcer specificity. Thus, no effects on alcohol-reinforced behaviors were observed following infusion in the nucleus accumbens (NACC)/caudate putamen (CPu), or on response maintained by saccharin. Parenteral-administered βCCt (1–40 mg/kg) was equally effective and selective in reducing alcohol-reinforced behaviors in P and HAD-1 rats. Additional tests of locomotor activity revealed that βCCt reversed the locomotor sedation produced by both chlordiazepoxide (10 mg/kg) and EtOH (1.25 g/kg), but was devoid of intrinsic effects when given alone. Studies in recombinant receptors expressed in Xenopus oocytes revealed that βCCt acted as a low-efficacy partial agonist at α3β3γ2 and α4β3γ2 receptors and as a low-efficacy inverse agonist at α1β3γ2, α2β3γ2, and α5β3γ2 receptors. The present study indicates that βCCt is capable of antagonizing the reinforcing and the sedative properties of alcohol. These anti-alcohol properties of βCCt are primarily mediated via the GABAA1 receptor. βCCt may represent a prototype of a pharmacotherapeutic agent to effectively reduce alcohol drinking behavior in human alcoholics.

Selective antagonism of the ataxic effects of zolpidem and triazolam by the GABAA/α1-preferring antagonist β-CCt in squirrel monkeys

Abstract Rationale. Delineation of the receptor mechanisms underlying the behavioral effects of benzodiazepines should allow for the development of drugs with improved clinical utility and reduced side effects. Objectives. The purpose of the present study was to investigate the role of GABAA/α1 receptors in the sedative and motor-impairing effects of benzodiazepines. Methods. Squirrel monkeys were tested with the GABAA/α1-preferring agonist zolpidem and the nonselective benzodiazepine agonist triazolam alone and in combination with the GABAA/α1-preferring antagonist β-CCt and the nonselective benzodiazepine antagonist flumazenil. During 30-min experimental sessions, all occurrences of normal behaviors like locomotion, environment- and self-directed behaviors, as well as side effects such as ataxia, rest and procumbent postures were scored. Results. Zolpidem and triazolam produced dose-dependent reductions in locomotion and environment-directed behavior and increased ataxia and procumbent posture. Triazolam, but not zolpidem, also engendered species-typical rest posture at some doses. Flumazenil antagonized all of the behavioral effects of zolpidem and triazolam, whereas β-CCt antagonized only zolpidem- and triazolam-induced ataxia. Conclusions. GABAA/α1 receptor mechanisms appear to play a key role in the ataxic effects of benzodiazepine agonists in squirrel monkeys, similar to recent results with transgenic mice. In contrast to the findings of these recent studies, GABAA mechanisms other than or in addition to those mediated at the α1 subunit may play a more important role in the sedative/hypnotic effects of benzodiazepines in squirrel monkeys.

Enantiospecific total synthesis of the enantiomer of the indole alkaloid affinisine

Abstract The enantiomer of affinisine has been synthesized (from l -tryptophan) with 100% diastereoselectivity via the asymmetric Pictet–Spengler reaction coupled with a Pd 0 (enolate mediated) coupling process. This enantiomer has also been converted into a key intermediate which provides a route to the enantiomers of both macroline and alstonerine following the previous work of LeQuesne.

Concise synthesis of optically active ring-A substituted tryptophans

A concise synthesis of optically active trytophan derivatives was developed via diastereoselective alkylation of the Schollkopf chiral auxiliary 4 to provide alkyne 2 which underwent palladium-catalyzed heteroannulation with iodoanilines 1 to furnish protected tryptophans 3. Hydrolysis and subsequent saponification of 3 provided the desired tryptophans 12 in good yields.

Efficient asymmetric synthesis of important tryptophan analogs for biological research via the Schöllkopf chiral auxiliary

An efficient method has been developed via the Schollkopf chiral auxiliary for the asymmetric synthesis of the important tryptophan analogs: l-isotryptophan, l-benzo[f]tryptophan and l-homotryptophan.

EFFECT OF THE LEAVING GROUP ON THE ALKYLATION DIASTEREOSELECTIVITY OF THE SCHOLLKOPF CHIRAL AUXILIARY

Tosylates, diphenylphosphates and bromides were employed to study the effect of the leaving group on the alkylation diastereoselectivity of the Schollkopf chiral auxiliary 1 at aliphatic, benzylic, propargylic and allylic electrophilic centers. The diastereoselectivity generally follows the pattern: diphenylphosphate > tosylate > bromide. In terms of both diastereoselectivity and yield, each leaving group possesses a different advantage.