Synthesis and structure-affinity relationship investigations of 5-heteroaryl-substituted analogues of the antipsychotic sertindole. A new class of highly selective alpha(1) adrenoceptor antagonists

J Med Chem. 2003 Jan 16;46(2):265-83. doi: 10.1021/jm020938y.

Abstract

A new class of 5-heteroaryl-substituted 1-(4-fluorophenyl)-3-(4-piperidinyl)-1H-indoles as highly selective and potentially CNS-active alpha 1-adrenoceptor antagonists is described. The compounds are derived from the antipsychotic sertindole. The structure-affinity relationships of the 5-heteroaryl substituents, and the substituents on the piperidine nitrogen atom were optimized with respect to affinity for alpha 1 adrenoceptors and selectivity in respect to dopamine (D(1-4)) and serotonin (5-HT(1A-1B) and 5-HT(2A,2C)) receptors. The most selective compound obtained, 3-[4-[1-(4-fluorophenyl)-5-(1-methyl-1,2,4-triazol-3-yl)-1H-indol-3-yl]-1-piperidinyl]propionitrile (15c), has affinities of 0.99, 3.2, and 9.0 nM for the alpha(1a), alpha(1b), and alpha(1d) adrenoceptor subtypes, respectively, and a selectivity for adrenergic alpha(1a) receptors in respect to dopamine D2, D3, and D4 and serotonin 5-HT(2A) and 5-HT(2C) higher than 900, comparable to the selectivity of prazosin. In addition, the compound is more than 150-fold selective in respect to serotonin 5-HT(1A) and 5-HT(1B) receptors. A new basic pharmacophore for alpha 1-adrenoceptor antagonists based on a previously reported pharmacophore model for dopamine D2 antagonist is suggested.

MeSH terms

  • Adrenergic alpha-Antagonists / chemical synthesis*
  • Adrenergic alpha-Antagonists / chemistry
  • Adrenergic alpha-Antagonists / pharmacology
  • Animals
  • Antipsychotic Agents / chemical synthesis*
  • Antipsychotic Agents / chemistry
  • Antipsychotic Agents / pharmacology
  • Azoles / chemical synthesis
  • Azoles / chemistry
  • Azoles / pharmacology
  • Brain / metabolism
  • Cell Line
  • Cricetinae
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • In Vitro Techniques
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Radioligand Assay
  • Rats
  • Receptors, Adrenergic, alpha-1 / drug effects*
  • Receptors, Adrenergic, alpha-1 / metabolism
  • Receptors, Dopamine / metabolism
  • Receptors, Serotonin / metabolism
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis*
  • Triazoles / chemistry
  • Triazoles / pharmacology

Substances

  • 3-(4-(1-(4-fluorophenyl)-5-(1-methyl-1,2,4-triazol-3-yl)-1H-indol-3-yl)-1-piperidinyl)propionitrile
  • Adrenergic alpha-Antagonists
  • Antipsychotic Agents
  • Azoles
  • Imidazoles
  • Indoles
  • Pyridines
  • Pyrimidines
  • Receptors, Adrenergic, alpha-1
  • Receptors, Dopamine
  • Receptors, Serotonin
  • Triazoles
  • sertindole