Synthesis and structure-activity relationships of a new model of arylpiperazines. 1. 2-[[4-(o-methoxyphenyl)piperazin-1-yl]methyl]-1, 3-dioxoperhydroimidazo[1,5-alpha]pyridine: a selective 5-HT1A receptor agonist

J Med Chem. 1996 Oct 25;39(22):4439-50. doi: 10.1021/jm960416g.

Abstract

A series of new bicyclohydantoin-arylpiperazines was prepared and evaluated for affinity at 5-HT1A, alpha 1, and D2 receptors. Most of the compounds showed very low affinity for D2 receptors, and most of them demonstrated moderate to high affinity for 5-HT1A and alpha 1 receptor binding sites. SAR observations indicated that the length of the alkyl chain between the arylpiperazine and the hydantoin moiety is of great importance for 5-HT1A/alpha 1 affinity and selectivity, n = 1 being the optimal value. Compound 1h, 2-[[4-(o-methoxyphenyl)piperazin-1-yl] methyl]-1,3-dioxoperhydroimidazo [1,5-alpha]pyridine, bound at 5-HT1A sites with nanomolar affinity (Ki = 31.7 nM) and high selectivity over alpha 1, D2, and 5-HT2A receptors (Ki > 1000, > 10 000, and > 1000 nM, respectively). Preliminary studies showed that this agent is probably functioning as a partial to full 5-HT1A agonist, and it displayed anxiolytic activity on the social interaction test in mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / metabolism
  • Animals
  • Behavior, Animal / drug effects
  • Body Temperature / drug effects
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Kinetics
  • Mice
  • Piperazines / chemical synthesis
  • Piperazines / chemistry*
  • Raclopride
  • Rats
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Adrenergic, alpha-1 / metabolism
  • Receptors, Dopamine D2 / metabolism
  • Receptors, Serotonin / metabolism*
  • Receptors, Serotonin, 5-HT1
  • Salicylamides / metabolism
  • Serotonin Receptor Agonists / chemical synthesis
  • Serotonin Receptor Agonists / chemistry*
  • Social Behavior
  • Structure-Activity Relationship

Substances

  • Piperazines
  • Receptor, Serotonin, 5-HT2A
  • Receptors, Adrenergic, alpha-1
  • Receptors, Dopamine D2
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT1
  • Salicylamides
  • Serotonin Receptor Agonists
  • Raclopride
  • 8-Hydroxy-2-(di-n-propylamino)tetralin