Alpha1-adrenoceptor antagonists. 6. Structural optimization of pyridazinone-arylpiperazines. Study of the influence on affinity and selectivity of cyclic substituents at the pyridazinone ring and alkoxy groups at the arylpiperazine moiety

J Med Chem. 2003 Jul 31;46(16):3555-8. doi: 10.1021/jm0307842.

Abstract

In continuing our search for selective alpha(1)-adrenoceptor (AR) antagonists, we have synthesized new alkoxyarylpiperazinylalkylpyridazinone derivatives. The new compounds were tested for their affinity toward alpha(1)- and alpha(2)-AR and toward the 5-HT(1A) receptor. alpha(1)-AR affinity data are in the subnanomolar range, with 3 showing an affinity of 0.052 nM, about 5-fold higher than prazosin. None of the studied compounds was found to be alpha(1)/alpha(2) selective, but 8 showed an interesting 5-HT(1A)/alpha(1) affinity ratio of 119.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-Antagonists / chemical synthesis*
  • Adrenergic alpha-Antagonists / chemistry
  • Adrenergic alpha-Antagonists / pharmacology
  • Animals
  • Binding Sites
  • Binding, Competitive
  • Cerebral Cortex / metabolism
  • In Vitro Techniques
  • Ligands
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Pyridazines / chemical synthesis*
  • Pyridazines / chemistry
  • Pyridazines / pharmacology
  • Rats
  • Receptors, Adrenergic, alpha-1 / drug effects*
  • Receptors, Adrenergic, alpha-1 / metabolism
  • Receptors, Adrenergic, alpha-2 / drug effects
  • Receptors, Adrenergic, alpha-2 / metabolism
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin / metabolism
  • Receptors, Serotonin, 5-HT1
  • Structure-Activity Relationship

Substances

  • Adrenergic alpha-Antagonists
  • Ligands
  • Piperazines
  • Pyridazines
  • Receptors, Adrenergic, alpha-1
  • Receptors, Adrenergic, alpha-2
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT1