Rollema Biomedical Consulting, 20 Holdridge Court, Mystic, CT, 06355, USA.
Hurst Neuropharmacology Consulting, 30 Brook Trail Road, Wayland, MA, 01778, USA.
Psychopharmacology (Berl). 2018 Sep;235(9):2479-2505. doi: 10.1007/s00213-018-4921-9. Epub 2018 Jul 7.
Two mechanisms underlie smoking cessation efficacies of α4β2* nicotinic acetylcholine receptor (nAChR) agonists: a "nicotine-like" agonist activity reduces craving by substituting for nicotine during a quit attempt, and a "nicotine-blocking" antagonist activity attenuates reinforcement by competing with inhaled nicotine during a relapse. To evaluate the contribution of each mechanism to clinical efficacy, we estimated the degree of agonist and antagonist activities of nicotine replacement therapy (NRT), varenicline, cytisine, and the discontinued nAChR agonists dianicline, ABT-418, ABT-089, CP-601927, and CP-601932, relative to the functional effects of nicotine from smoking.
Functional activities that occur in vivo with clinical doses were predicted from literature data on binding and functional potencies at the target α4β2 nAChR, as well as at α6β2* nAChRs, and from estimates of free drug exposures in human brain. Agonist activity is comprised of nAChR activation and desensitization, which were expressed as percentages of desensitization and activation by nicotine from smoking. Antagonist activity was expressed as the reduction in nAChR occupancy by nicotine during smoking in the presence of an agonist.
Comparisons with odds ratios at end of treatment suggest that extensive α4β2 and α6β2* nAChR desensitization combined with α6β2* nAChR activation at similar levels as nicotine from smoking is associated with clinical efficacy (NRT, varenicline, cytisine, ABT-418). Effective competition with inhaled nicotine for α4β2 and α6β2* nAChRs further improves clinical efficacy (varenicline). Other discontinued nAChR agonists have lower agonist and antagonist activities at α4β2 nAChRs and are inactive or less efficacious than NRT (dianicline, ABT-089, CP-601927, CP-601932).
Three pharmacological effects appear to be key factors underlying smoking cessation efficacy: the degree of activation of α6β2* nAChRs, desensitization of α4β2 and α6β2* nAChRs (agonist activity), and the reduction of nicotine occupancy at α4β2 and α6β2* nAChRs (antagonist activity). No single activity is dominant, and the level of smoking cessation efficacy depends on the profile of these activities achieved at clinical doses. While adequate agonist activity alone seems sufficient for a clinical effect (e.g., NRT, cytisine), clinical efficacy is improved with substantial competitive antagonism of α4β2 nAChRs, i.e., if the drug has a dual agonist-antagonist mechanism of action (e.g., varenicline).
α4β2*烟碱型乙酰胆碱受体(nAChR)激动剂戒烟疗效的两种机制：“类尼古丁”激动剂通过在戒烟尝试期间替代尼古丁来减少渴望，“尼古丁阻断”拮抗剂通过与吸入尼古丁竞争来减轻复吸时的强化作用。为了评估每种机制对临床疗效的贡献，我们估计了尼古丁替代疗法(NRT)、伐伦克林、烟碱、以及已停产的 nAChR 激动剂二氨替林、ABT-418、ABT-089、CP-601927 和 CP-601932 的激动剂和拮抗剂活性，相对于吸烟时尼古丁的功能效应。
从文献中关于在目标 α4β2 nAChR 以及 α6β2*nAChR 上的结合和功能效力的文献数据，以及从人类大脑中药物游离暴露的估计中，预测了在临床剂量下体内发生的功能活性。激动剂活性包括烟碱型乙酰胆碱受体的激活和脱敏，这通过吸烟时尼古丁引起的脱敏和激活的百分比来表示。拮抗剂活性表示在存在激动剂时，尼古丁对烟碱型乙酰胆碱受体的占有率的降低。
与治疗结束时的比值比比较表明，广泛的α4β2 和α6β2烟碱型乙酰胆碱受体脱敏与吸烟时尼古丁引起的脱敏和激活水平相似，与临床疗效相关（NRT、伐伦克林、烟碱、ABT-418）。与吸入尼古丁有效竞争α4β2 和α6β2烟碱型乙酰胆碱受体进一步提高了临床疗效（伐伦克林）。其他已停产的 nAChR 激动剂在 α4β2 nAChR 上的激动剂和拮抗剂活性较低，且无活性或疗效低于 NRT（二氨替林、ABT-089、CP-601927、CP-601932）。
三种药理学作用似乎是戒烟疗效的关键因素：α6β2烟碱型乙酰胆碱受体的激活程度、α4β2 和α6β2烟碱型乙酰胆碱受体的脱敏（激动剂活性）以及α4β2 和α6β2*烟碱型乙酰胆碱受体上尼古丁占有率的降低（拮抗剂活性）。没有单一的活性占主导地位，临床疗效的水平取决于在临床剂量下达到的这些活性的特征。虽然足够的激动剂活性本身似乎足以产生临床效果（例如，NRT、烟碱），但如果药物具有双重激动剂-拮抗剂作用机制（例如，伐伦克林），则通过对α4β2 烟碱型乙酰胆碱受体的竞争拮抗作用可以改善临床疗效。
