AMOP‐H‐OH (sazetidine‐A; 6‐[5‐(azetidin‐2‐ylmethoxy)pyridin‐3‐yl]hex‐5‐yn‐1‐ol) and some sulfur‐bearing analogues were tested for their activities in vitro against human α4β2‐, α4β4‐, α3β4*‐ and α1*‐nicotinic acetylcholine receptors (nAChRs). AMOP‐H‐OH was also assessed in an antidepressant efficacy model. AMOP‐H‐OH and some of its analogues have high potency and selectivity for α4β2‐nAChRs over other nAChR subtypes. Effects are manifested as partial agonism, perhaps reflecting selectivity for high sensitivity (α4)₃(β2)₂‐nAChRs. More prolonged exposure to AMOP‐H‐OH and its analogues produces inhibition of subsequent responses to acute challenges with full nicotinic agonists, again selectively for α4β2‐nAChRs over other nAChR subtypes. The inhibition is mediated either via antagonism or desensitization of nAChR function, but the degree of inhibition of α4β2‐nAChRs is limited by the partial agonist activity of the drugs. Certain aspects of the in vitro pharmacology suggest that AMOP‐H‐OH and some of its analogues have a set of binding sites on α4β2‐nAChRs that are distinct from those for full agonists. The in vitro pharmacological profile suggests that peripheral side effects of AMOP‐H‐OH or its analogues would be minimal and that their behavioral effects would be dominated by central nAChR actions. AMOP‐H‐OH also has profound and high potency antidepressant‐like effects in the forced swim test. The net action of prolonged exposure to AMOP‐H‐OH or its analogues, as for nicotine, seems to be a selective decrease in α4β2‐nAChR function. Inactivation of nAChRs may be a common neurochemical endpoint for nicotine dependence, its treatment, and some of its manifestations, including relief from depression.

中文翻译：

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基于 6-[5-(氮杂环丁烷-2-基甲氧基)pyridin-3-yl]hex-5-yn-1-ol (AMOP-H-OH) 的烟碱配体的化学和药理学可能用于抑郁症

测试了 AMOP-H-OH（sazetidine-A；6-[5-(azetidin-2-ylmethoxy)pyridin-3-yl]hex-5-yn-1-ol）和一些含硫类似物的活性体外抗人 α4β2-、α4β4-、α3β4*- 和 α1*-烟碱乙酰胆碱受体 (nAChRs)。AMOP-H-OH 也在抗抑郁药效模型中进行了评估。AMOP-H-OH 及其一些类似物对 α4β2-nAChR 的效力和选择性高于其他 nAChR 亚型。效应表现为部分激动，可能反映了对高灵敏度的选择性 (α4) ₃ (β2) ₂-nAChR。更长时间地暴露于 AMOP-H-OH 及其类似物会抑制随后对完全烟碱激动剂的急性挑战的反应，再次选择性地针对 α4β2-nAChRs，而不是其他 nAChR 亚型。这种抑制是通过 nAChR 功能的拮抗或脱敏作用介导的，但 α4β2-nAChR 的抑制程度受到药物的部分激动剂活性的限制。体外药理学的某些方面表明 AMOP-H-OH 及其一些类似物在 α4β2-nAChR 上具有一组与完全激动剂不同的结合位点。体外药理学特征表明 AMOP-H-OH 或其类似物的外周副作用很小，并且它们的行为影响将由中枢 nAChR 作用主导。AMOP-H-OH 在强迫游泳试验中也具有显着和高效的抗抑郁样作用。与尼古丁一样，长期接触 AMOP-H-OH 或其类似物的净作用似乎是选择性降低 α4β2-nAChR 功能。nAChR 的失活可能是尼古丁依赖、其治疗及其某些表现（包括缓解抑郁症）的常见神经化学终点。