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Comparisons of hallucinogenic phenylisopropylamine binding affinities at cloned human 5-HT2A, 5-HT2B and 5-HT2C receptors

  • D. L. Nelson
  • V. L. Lucaites
  • D. B. Wainscott
  • R. A. Glennon
Original article

Abstract

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.

Key words Hallucinogenic agents Serotonin receptors 5-HT2 receptor subpopulations 

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Copyright information

© Springer-Verlag Berlin Heidelberg 1999

Authors and Affiliations

  • D. L. Nelson
    • 1
  • V. L. Lucaites
    • 1
  • D. B. Wainscott
    • 1
  • R. A. Glennon
    • 2
  1. 1.Neuroscience Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USAIN
  2. 2.Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298-0540, USA e-mail: glennon@hsc.vcu.edu, Fax: +1-804-8287404US

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