Identification of a dihydropyridine as a potent alpha1a adrenoceptor-selective antagonist that inhibits phenylephrine-induced contraction of the human prostate

J Med Chem. 1998 Jul 2;41(14):2643-50. doi: 10.1021/jm980077m.

Abstract

A number of novel dihydropyridine derivatives based upon 1, 4-dihydro-3-(methoxycarbonyl)-2, 6-dimethyl-4-(4-nitrophenyl)-5-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (4) have been synthesized and tested at cloned human alpha adrenoceptors as well as the rat L-type calcium channel. Within this compound series, 5-(aminocarbonyl)-1,4-dihydro-2, 6-dimethyl-4-(4-nitrophenyl)-3-((3-(4, 4-diphenylpiperidin-1-yl)propyl)aminocarbonyl)pyridine (19) displayed good binding affinity and selectivity for the alpha1a adrenoceptor (pKi = 8.73) and potently inhibited (pA2 = 9.23) phenylephrine-induced contraction of the human prostate.

MeSH terms

  • Adrenergic alpha-Agonists / pharmacology*
  • Adrenergic alpha-Antagonists / pharmacology*
  • Aged
  • Aged, 80 and over
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Calcium Channels / drug effects
  • Humans
  • In Vitro Techniques
  • Male
  • Middle Aged
  • Muscle Contraction / drug effects
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / physiopathology
  • Phenylephrine / pharmacology*
  • Piperidines* / chemical synthesis
  • Piperidines* / metabolism
  • Piperidines* / pharmacology
  • Prostate / drug effects*
  • Prostate / physiopathology
  • Prostatic Hyperplasia / physiopathology
  • Pyridines* / chemical synthesis
  • Pyridines* / metabolism
  • Pyridines* / pharmacology
  • Rats
  • Receptors, Adrenergic, alpha-1 / drug effects*

Substances

  • 5-(aminocarbonyl)-1,4-dihydro-2,6-dimethyl-4-(4-nitrophenyl)-(3-(4,4-diphenylpiperidin-1-yl)propyl)
  • ADRA1A protein, human
  • Adra1a protein, rat
  • Adrenergic alpha-Agonists
  • Adrenergic alpha-Antagonists
  • Calcium Channels
  • Piperidines
  • Pyridines
  • Receptors, Adrenergic, alpha-1
  • Phenylephrine