Conformationally Defined Adrenergic Agents. 1. Design and Synthesis of Novel Alpha 2 Selective Adrenergic Agents: Electrostatic Repulsion Based Conformational Prototypes

J Med Chem. 1985 Oct;28(10):1398-404. doi: 10.1021/jm00148a005.

Abstract

A previous report of the adrenergic selectivity of 2- and 6-fluoronorepinephrine prompted us to formulate a hypothesis that accounted for this selectivity on the basis of a conformational preference induced by electrostatic repulsion between the aromatic fluorine atom and the side-chain hydroxyl group. A series of nitrogen-substituted catechol (aminomethyl)benzocyclobutenes, indanes, tetralins, and benzocycloheptenes were prepared, and when their radioligand binding affinities were determined, it was found that the overall pattern of binding affinity results supported the electrostatic repulsion hypothesis. The radioligand binding assay also revealed several highly alpha 2 selective adrenergic agents among these compounds, with the binding selectivity maximizing for compounds having nitrogen substituted with a group no larger than methyl and having a five-membered carbocyclic ring (i.e., 16, 17, and 19).

MeSH terms

  • Adrenergic alpha-Agonists / chemical synthesis*
  • Adrenergic alpha-Agonists / metabolism
  • Animals
  • Chemical Phenomena
  • Chemistry, Physical
  • Electricity
  • Male
  • Molecular Conformation
  • Motion
  • Radioligand Assay
  • Rats
  • Receptors, Adrenergic, alpha / classification
  • Receptors, Adrenergic, alpha / metabolism*
  • Structure-Activity Relationship

Substances

  • Adrenergic alpha-Agonists
  • Receptors, Adrenergic, alpha