Selectivity of serotonergic drugs for multiple brain serotonin receptors. Role of [3H]-4-bromo-2,5-dimethoxyphenylisopropylamine ([3H]DOB), a 5-HT2 agonist radioligand

Biochem Pharmacol. 1987 Oct 1;36(19):3265-71. doi: 10.1016/0006-2952(87)90643-5.


The affinities of putative serotonin receptor agonists and antagonists for 5-HT1A, 5-HT1B, 5-HT1C, and 5-HT2 receptors were assayed using radioligand binding assays. The 5-HT1 sites were labeled with the agonist radioligands [3H]-8-hydroxy-2-(di-n-propylamino)-tetralin [3H]-8-OH-DPAT, [3H]-5-HT, and [3H]mesulergine. The 5-HT2 receptor was labeled with the antagonist radioligand [3H]ketanserin or the agonist radioligand [3H]-4-bromo-2,5-dimethoxyphenylisopropylamine ([3H]DOB). The apparent 5-HT1 receptor selectivity of agonist compounds was found to be 50- to 100-fold higher when the 5-HT2 receptor affinity was determined using the antagonist radioligand [3H]ketanserin than when the agonist radioligand [3H]DOB was used. Quipazine, a putative specific 5-HT2 agonist, appeared to be only 3-fold more potent at 5-HT2 than at 5-HT1A receptors when [3H]ketanserin was used as the 5-HT2 radioligand. When [3H]DOB was used as the 5-HT2 radioligand, quipazine was determined to be 100-fold more potent at 5-HT2 receptors than at 5-HT1A receptors. 1-(3-trifluoromethylphenyl)piperazine (TFMPP), a putative specific 5-HT1B receptor agonist was apparently 10-fold more potent at 5-HT1B receptors than at 5-HT2 receptors when [3H]ketanserin was used as the 5-HT2 radioligand. When [3H]DOB was used as the 5-HT2 radioligand, TFMPP was found to be equipotent at 5-HT1B and 5-HT2 receptors. Using the 5-HT2 antagonist radioligand [3H]ketanserin, a similar pattern of underestimating 5-HT2 receptor selectivity and/or overestimating 5-HT1A or 5-HT1B receptor selectivity was observed for a series of serotonin receptor agonists. Antagonist receptor selectivity was not affected significantly by the nature of the 5-HT2 receptor assay used. These data indicate that, by using an antagonist radioligand to label 5-HT2 receptors and agonist radioligands to label 5-HT1 receptors, the 5-HT1 receptor selectivity may be overestimated. This may be an especially severe problem in serotonin drug development as drugs that interact potently with 5-HT2 receptors have been reported to be psychoactive and/or hallucinogenic.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amphetamines / metabolism*
  • Animals
  • Brain / metabolism*
  • DOM 2,5-Dimethoxy-4-Methylamphetamine / analogs & derivatives
  • DOM 2,5-Dimethoxy-4-Methylamphetamine / metabolism*
  • In Vitro Techniques
  • Ketanserin / metabolism
  • Ligands
  • Male
  • Piperazines / metabolism
  • Rats
  • Rats, Inbred Strains
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin / metabolism*
  • Serotonin Antagonists / pharmacology
  • Tritium


  • Amphetamines
  • Ligands
  • Piperazines
  • Receptors, Serotonin
  • Serotonin Antagonists
  • Tritium
  • DOM 2,5-Dimethoxy-4-Methylamphetamine
  • 1-(3-trifluoromethylphenyl)piperazine
  • 2,5-dimethoxy-4-bromoamphetamine
  • Ketanserin