Design, Synthesis, and Biological Activity of Prazosin-Related Antagonists. Role of the Piperazine and Furan Units of Prazosin on the Selectivity for alpha1-adrenoreceptor Subtypes

J Med Chem. 1998 Nov 19;41(24):4844-53. doi: 10.1021/jm9810654.

Abstract

Prazosin-related quinazolines 4-20 were synthesized, and their biological profiles at alpha1-adrenoreceptor subtypes were assessed by functional experiments in isolated rat vas deferens (alpha1A), spleen (alpha1B), and aorta (alpha1D) and by binding assays in CHO cells expressing human cloned alpha1-adrenoreceptor subtypes. The replacement of piperazine and furan units of prazosin (1) by 1, 6-hexanediamine and phenyl moieties, respectively, affording 3-20, markedly affected both affinity and selectivity for alpha1-adrenoreceptor subtypes in functional experiments. Cystazosin (3), bearing a cystamine moiety, was a selective alpha1D-adrenoreceptor antagonist being 1 order of magnitude more potent at alpha1D-adrenoreceptors (pA2, 8.54 +/- 0.02) than at the alpha1A- (pA2, 7.53 +/- 0.01) and alpha1B-subtypes (pA2, 7.49 +/- 0. 01). The insertion of substituents on the furan ring of 3, as in compounds 4 and 5, did not improve the selectivity profile. The simultaneous replacement of both piperazine and furan rings of 1 gave 8 which resulted in a potent, selective alpha1B-adrenoreceptor antagonist (85- and 15-fold more potent than at alpha1A- and alpha1D-subtypes, respectively). The insertion of substituents on the benzene ring of 8 affected, according to the type and the position of the substituent, affinity and selectivity for alpha1-adrenoreceptors. Consequently, the insertion of appropriate substituents in the phenyl ring of 8 may represent the basis of designing new selective ligands for alpha1-adrenoreceptor subtypes. Interestingly, the finding that polyamines 11, 16, and 20, bearing a 1,6-hexanediamine moiety, retained high affinity for alpha1-adrenoreceptor subtypes suggests that the substituent did not give rise to negative interactions with the receptor. Finally, binding assays performed with selected quinazolines (2, 3, and 14) produced affinity results, which were not in agreement with the selectivity profiles obtained from functional experiments. This rather surprising and unexpected finding may be explained by considering neutral and negative antagonism.

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
  • Aorta, Thoracic / drug effects
  • Aorta, Thoracic / physiology
  • CHO Cells
  • Cricetinae
  • Drug Design
  • Furans / chemistry*
  • Humans
  • In Vitro Techniques
  • Male
  • Muscle Contraction / drug effects
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / physiology
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / physiology
  • Piperazine
  • Piperazines / chemistry*
  • Prazosin / analogs & derivatives*
  • Prazosin / chemical synthesis*
  • Prazosin / chemistry
  • Prazosin / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, alpha-1 / biosynthesis
  • Receptors, Adrenergic, alpha-1 / drug effects*
  • Spleen / drug effects
  • Spleen / physiology
  • Structure-Activity Relationship
  • Vas Deferens / drug effects
  • Vas Deferens / physiology

Substances

  • Adrenergic alpha-Antagonists
  • Furans
  • Piperazines
  • Receptors, Adrenergic, alpha-1
  • Piperazine
  • furan
  • Prazosin