Nelson D L, Lucaites V L, Wainscott D B, Glennon R A
Neuroscience Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Naunyn Schmiedebergs Arch Pharmacol. 1999 Jan;359(1):1-6. doi: 10.1007/pl00005315.
Since the classical hallucinogens were initially reported to produce their behavioral effects via a 5-HT2 agonist mechanism (i.e., the 5-HT2 hypothesis of hallucinogen action), 5-HT2 receptors have been demonstrated to represent a family of receptors that consists of three distinct subpopulations: 5-HT2A, 5-HT2B, and 5-HT2C receptors. Today, there is greater support for 5-HT2A than for 5-HT2C receptor involvement in the behavioral effects evoked by these agents. However, with the recent discovery of 5-HT2B receptors, a new question arises: do classical hallucinogens bind at 5-HT2B receptors? In the present study we examined and compared the binding of 17 phenylisopropylamines at human 5-HT2A, 5-HT2B, and 5-HT2C receptors. Although there was a notable positive correlation (r>0.9) between the affinities of the agents at all three populations of 5-HT2 receptors, structural modification resulted only in small differences in 5-HT2B receptor affinity such that the range of affinities was only about 50-fold. As with 5-HT2A and 5-HT2C receptor affinity, there is a significant correlation (r>0.9, n=8) between 5-HT2B receptor affinity and human hallucinogenic potency. Nevertheless, given that 5-HT2A and 5-HT2A/2C antagonists - antagonists with low affinity for 5-HT2B receptors - have been previously shown to block the stimulus effects of phenylisopropylamine hallucinogens, it is likely that 5-HT2A receptors play a more prominent role than 5-HT2B and 5-HT2C receptors in mediating such effects despite the affinity of these agents for all three 5-HT2 receptor subpopulations.
由于最初报道经典致幻剂是通过5-羟色胺2（5-HT2）激动剂机制产生其行为效应的（即致幻剂作用的5-HT2假说），现已证明5-HT2受体代表一个由三个不同亚群组成的受体家族：5-HT2A、5-HT2B和5-HT2C受体。如今，对于5-HT2A受体参与这些药物诱发的行为效应的支持，比5-HT2C受体更多。然而，随着5-HT2B受体的最近发现，一个新问题出现了：经典致幻剂是否与5-HT2B受体结合？在本研究中，我们检测并比较了17种苯异丙胺在人5-HT2A、5-HT2B和5-HT2C受体上的结合情况。尽管这些药物在所有三个5-HT2受体亚群上的亲和力之间存在显著正相关（r>0.9），但结构修饰仅导致5-HT2B受体亲和力的微小差异，使得亲和力范围仅约为50倍。与5-HT2A和5-HT2C受体亲和力一样，5-HT2B受体亲和力与人致幻效力之间存在显著相关性（r>0.9，n = 8）。然而，鉴于5-HT2A和5-HT2A/2C拮抗剂——对5-HT2B受体亲和力低的拮抗剂——先前已被证明可阻断苯异丙胺致幻剂的刺激效应，尽管这些药物对所有三个5-HT2受体亚群都有亲和力，但在介导此类效应方面，5-HT2A受体可能比5-HT2B和5-HT2C受体发挥更突出的作用。
