Analogues of the 5-HT1A Serotonin Antagonist 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine With Reduced Alpha 1-adrenergic Affinity

J Med Chem. 1991 Aug;34(8):2633-8. doi: 10.1021/jm00112a043.

Abstract

1-(2-Methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine (NAN-190; 1a) is a putative postsynaptic 5-HT1A serotonin antagonist. This high affinity ligand (Ki = 0.6 nM), although selective for 5-HT1A versus other 5-HT receptors, binds with nearly equal affinity at alpha 1-adrenergic receptors (Ki = 0.8 nm). Structure-affinity relationship studies were conducted in order to achieve an improved selectivity. Replacement of the phthalimide moiety by substituted benzamides led to retention of 5-HT1A affinity but to no improvement in selectivity, whereas replacement by alkyl amides proved beneficial, leading to an improvement in affinity and selectivity. Branching alpha to the amide carbonyl group and increased bulkiness of the alkyl moiety further improved 5-HT1A affinity and selectivity. 4-[4-(1-Adamantanecarboxamido)butyl]-1- (2-methoxyphenyl)piperazine (2j) was found to bind at 5-HT1A sites with high affinity (Ki = 0.4 nM) and with a 160-fold selectivity over alpha 1-adrenergic sites. Preliminary studies show that this agent retains antagonist activity as determined in a 5-HT1A-coupled adenylyl cyclase assay. Further functional studies are warranted to fully characterize this agent.

Publication types

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

MeSH terms

  • Adamantane / analogs & derivatives
  • Adamantane / chemical synthesis
  • Adamantane / metabolism
  • Adamantane / pharmacology
  • Adenylyl Cyclase Inhibitors
  • Amides / chemistry
  • Animals
  • Chemical Phenomena
  • Chemistry
  • Hippocampus / enzymology
  • Molecular Structure
  • Piperazines / chemical synthesis
  • Piperazines / chemistry*
  • Piperazines / metabolism
  • Piperazines / pharmacology
  • Rats
  • Rats, Inbred Strains
  • Receptors, Adrenergic, alpha / metabolism*
  • Receptors, Serotonin / metabolism
  • Serotonin Antagonists / chemical synthesis*
  • Serotonin Antagonists / metabolism
  • Serotonin Antagonists / pharmacology
  • Structure-Activity Relationship

Substances

  • Adenylyl Cyclase Inhibitors
  • Amides
  • Piperazines
  • Receptors, Adrenergic, alpha
  • Receptors, Serotonin
  • Serotonin Antagonists
  • 1-(2-methoxyphenyl)-4-(4-(2-phthalimido)butyl)piperazine
  • 4-(4-(1-adamantanecarboxamido)butyl)-1-(2-methoxyphenyl)piperazine
  • Adamantane