Positive allosteric modulators of the GABAB receptor: a new class of ligands with therapeutic potential for alcohol use disorder

IF 2.1 4区医学 Q3 SUBSTANCE ABUSE

Alcohol and alcoholism Pub Date : 2024-04-03 DOI:10.1093/alcalc/agae018

Giancarlo Colombo

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引用次数: 0

Abstract

Background Positive allosteric modulators (PAMs) of the GABAB receptor constitute a new class of GABAB-receptor ligands. GABAB PAMs reproduce several pharmacological effects of the orthosteric GABAB receptor agonist, baclofen, although displaying a better safety profile. Aims This paper reviews the reducing or, frequently, even suppressing effects of all GABAB PAMs tested to date on multiple alcohol-related behaviours in laboratory rodents exposed to validated experimental models of human alcohol use disorder. Results Acute or repeated treatment with CGP7930, GS39783, BHF177, rac-BHFF, ADX71441, CMPPE, COR659, ASP8062, KK-92A, and ORM-27669 reduced excessive alcohol drinking, relapse- and binge-like drinking, operant alcohol self-administration, reinstatement of alcohol seeking, and alcohol-induced conditioned place preference in rats and mice. Conclusions These effects closely mirrored those of baclofen; notably, they were associated to remarkably lower levels of tolerance and toxicity. The recent transition of ASP8062 to clinical testing will soon prove whether these highly consistent preclinical data translate to AUD patients.

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GABAB 受体的正性异构调节剂：一类具有治疗酒精使用障碍潜力的新型配体

背景 GABAB 受体的正性异位调节剂（PAMs）是一类新的 GABAB 受体配体。GABAB PAMs 可再现正交 GABAB 受体激动剂巴氯芬的多种药理作用，但具有更好的安全性。目的本文回顾了迄今为止测试过的所有 GABAB PAMs 对暴露于人类酒精使用障碍验证实验模型的实验室啮齿动物的多种酒精相关行为的降低甚至抑制作用。结果使用 CGP7930、GS39783、BHF177、rac-BHFF、ADX71441、CMPPE、COR659、ASP8062、KK-92A 和 ORM-27669 对大鼠和小鼠进行急性或重复治疗可减少过度饮酒、复饮和狂饮、操作性酒精自我给药、酒精寻求的恢复和酒精诱导的条件性位置偏好。结论这些效果与巴氯芬的效果非常相似；值得注意的是，这些效果与明显较低的耐受性和毒性有关。ASP8062 最近已进入临床试验阶段，不久将证明这些高度一致的临床前数据是否适用于 AUD 患者。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Alcohol and alcoholism 医学-药物滥用

CiteScore

4.70

自引率

3.60%

发文量

审稿时长

4-8 weeks

期刊介绍： About the Journal Alcohol and Alcoholism publishes papers on the biomedical, psychological, and sociological aspects of alcoholism and alcohol research, provided that they make a new and significant contribution to knowledge in the field. Papers include new results obtained experimentally, descriptions of new experimental (including clinical) methods of importance to the field of alcohol research and treatment, or new interpretations of existing results. Theoretical contributions are considered equally with papers dealing with experimental work provided that such theoretical contributions are not of a largely speculative or philosophical nature.