Novel 4-alkyl-1-arylpiperazines and 1,2,3,4-tetrahydroisoquinolines containing diphenylmethylamino or diphenylmethoxy fragment with differentiated 5-HT1A/5-HT2A/D2 receptor activity

Pol J Pharmacol. 2003 Jul-Aug;55(4):543-52.

Abstract

Two series of 4-alkyl-1-arylpiperazines (1-4) and 1,2,3,4-tetrahydroiso-quinolines (5, 6) with diphenylmethylamino (series a) or diphenylmethoxy (series b) fragment were synthesized in order to obtain potential ligands of 5-HT1A and/or 5-HT2A and dopamine D2 receptors. Four new arylpiperazines (1a, 3a, 1b, 3b) were found to demonstrate high 5-HT1A receptor affinity (Ki = 1.5-35 nM); among them, 3a exhibited satisfactory 5-HT2A receptor affinity (Ki = 74 nM). Only compounds 1b and 2b showed moderate affinity for D2 receptor sites (Ki = 123 and 128 nM, respectively). Compounds 1a, 3a, 1b and 3b were investigated in vivo to determine their functional activity at 5-HT1A receptors; additionally, 3a was tested for 5-HT2A receptor activity. Derivatives 1a, 1b and 3b produced effects characteristic of antagonists of postsynaptic 5-HT1A receptors. Moreover, 1b exhibited features of an agonist of presynaptic 5-HT1A receptors, while 3a behaved like a partial agonist of postsynaptic 5-HT1A sites. The latter derivative may also be classified as a 5-HT2A receptor antagonist. Thus, novel potent 5-HT1A receptor ligands were successfully obtained, and the most promising compound 3a showed mixed 5-HT1A/5-HT2A receptor activity in in vitro and in vivo tests.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal / drug effects
  • Binding, Competitive
  • Body Temperature / drug effects
  • Dopamine Agents / chemistry
  • Dopamine Agents / metabolism
  • Dopamine Agents / pharmacology
  • Dose-Response Relationship, Drug
  • Male
  • Mice
  • Molecular Structure
  • Piperazines / chemistry
  • Piperazines / metabolism*
  • Piperazines / pharmacology
  • Rats
  • Rats, Wistar
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Receptor, Serotonin, 5-HT2A / metabolism*
  • Receptors, Dopamine D2 / metabolism*
  • Serotonin Agents / chemistry
  • Serotonin Agents / metabolism
  • Serotonin Agents / pharmacology
  • Structure-Activity Relationship
  • Tetrahydroisoquinolines / chemistry
  • Tetrahydroisoquinolines / metabolism*
  • Tetrahydroisoquinolines / pharmacology
  • Time Factors

Substances

  • Dopamine Agents
  • Piperazines
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Dopamine D2
  • Serotonin Agents
  • Tetrahydroisoquinolines
  • Receptor, Serotonin, 5-HT1A