Arias Hugo R, Gumilar Fernanda, Rosenberg Avraham, Targowska-Duda Katarzyna M, Feuerbach Dominik, Jozwiak Krzysztof, Moaddel Ruin, Wainer Irving W, Bouzat Cecilia
Department of Pharmaceutical Sciences, College of Pharmacy, Midwestern University, Glendale, Arizona 85308, USA.
Biochemistry. 2009 Jun 2;48(21):4506-18. doi: 10.1021/bi802206k.
To characterize the binding sites and the mechanisms of inhibition of bupropion on muscle-type nicotinic acetylcholine receptors (AChRs), structural and functional approaches were used. The results established that bupropion (a) inhibits epibatidine-induced Ca(2+) influx in embryonic muscle AChRs, (b) inhibits adult muscle AChR macroscopic currents in the resting/activatable state with approximately 100-fold higher potency compared to that in the open state, (c) increases the desensitization rate of adult muscle AChRs from the open state and impairs channel opening from the resting state, (d) inhibits binding of [(3)H]TCP and [(3)H]imipramine to the desensitized/carbamylcholine-bound Torpedo AChR with higher affinity compared to the resting/alpha-bungarotoxin-bound AChR, (e) binds to the Torpedo AChR in either state mainly by an entropy-driven process, and (f) interacts with a binding domain located between the serine (position 6') and valine (position 13') rings, by a network of van der Waals, hydrogen bond, and polar interactions. Collectively, our data indicate that bupropion first binds to the resting AChR, decreasing the probability of ion channel opening. The remnant fraction of open ion channels is subsequently decreased by accelerating the desensitization process. Bupropion interacts with a luminal binding domain shared with PCP that is located between the serine and valine rings, and this interaction is mediated mainly by an entropy-driven process.
为了表征安非他酮对肌肉型烟碱型乙酰胆碱受体（AChRs）的结合位点及抑制机制，采用了结构和功能研究方法。结果表明，安非他酮（a）抑制埃博霉素诱导的胚胎肌肉AChRs中Ca(2+)内流；（b）抑制静息/可激活状态下成年肌肉AChR的宏观电流，其效力比开放状态下高约100倍；（c）增加成年肌肉AChRs从开放状态的脱敏速率，并损害从静息状态的通道开放；（d）与脱敏/氨甲酰胆碱结合的电鳐AChR相比，安非他酮以更高的亲和力抑制[(3)H]TCP和[(3)H]丙咪嗪与静息/α-银环蛇毒素结合的AChR的结合；（e）在任一状态下主要通过熵驱动过程与电鳐AChR结合；（f）通过范德华力、氢键和极性相互作用网络与位于丝氨酸（6'位）和缬氨酸（13'位）环之间的结合域相互作用。总体而言，我们的数据表明，安非他酮首先与静息AChR结合，降低离子通道开放的概率。随后，通过加速脱敏过程，开放离子通道的剩余部分减少。安非他酮与位于丝氨酸和缬氨酸环之间的、与苯环己哌啶共享的腔内结合域相互作用，这种相互作用主要由熵驱动过程介导。
