Synthesis and Structure-Activity Relationship of Fluoro Analogues of 8-{2-[4-(4-methoxyphenyl)piperazin-1yl]ethyl}-8-azaspiro[4.5]decane-7,9-dione as Selective alpha(1d)-adrenergic Receptor Antagonists

J Med Chem. 2005 Apr 21;48(8):3076-9. doi: 10.1021/jm0491391.

Abstract

We have discovered high-affinity antagonists (exemplified by 11 and 12) that are the most selective for alpha(1d)-adrenergic receptors (alpha(1d)-AR) reported to date. In cloned receptor assay systems, 12 displays at least 95-fold selectivity for the alpha(1d)-AR over all other G-protein-coupled receptors tested, and the subtype selectivity of 11 was confirmed in pharmacologically defined isolated tissue preparations.

Publication types

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

MeSH terms

  • Adrenergic alpha-1 Receptor Antagonists*
  • Animals
  • Aorta, Thoracic / drug effects
  • Aorta, Thoracic / physiology
  • Humans
  • In Vitro Techniques
  • Male
  • Muscle Contraction / drug effects
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / physiology
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Radioligand Assay
  • Rats
  • Receptors, Adrenergic, alpha-1 / physiology
  • Spiro Compounds / chemical synthesis*
  • Spiro Compounds / chemistry
  • Spiro Compounds / pharmacology
  • Spleen / drug effects
  • Spleen / physiology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Vas Deferens / drug effects
  • Vas Deferens / physiology

Substances

  • 8-(2-(4-(2,4,5-trifluorophenyl)piperazin-1-yl)-1-methylethyl)-8-azaspiro(4.5)decane-7,9-dione
  • 8-(2-(4-(2,4,5-trifluorophenyl)piperazin-1-yl)ethyl)-8-azaspiro(4.5)decane-7,9-dione
  • ADRA1D protein, human
  • Adrenergic alpha-1 Receptor Antagonists
  • Piperazines
  • Receptors, Adrenergic, alpha-1
  • Spiro Compounds