Medetomidine analogs as alpha 2-adrenergic ligands. 2. Design, synthesis, and biological activity of conformationally restricted naphthalene derivatives of medetomidine

J Med Chem. 1996 Jul 19;39(15):3001-13. doi: 10.1021/jm9506074.


A new series of naphthalene analogs of medetomidine have been prepared and evaluated for their alpha-adrenergic activities. The methylnaphthyl analog 5a showed significant selectivity for alpha 2-adrenoceptors and behaved as a partial alpha 1-agonist in rat aorta preparations. In contrast, the Z-ethylene analog 8c was alpha 1-selective and behaved as a potent alpha 1-antagonist. Two rigid analogs (6 and 7) exhibited large differences in binding affinities at alpha 1-VS alpha 2-receptors, indicating that the conformational flexibility of 5a is important for the fulfillment of the alpha-adrenergic activities. Molecular modeling studies began with conformational analysis of classical phenethylamines and medetomidine analogs. Superimposition of medetomidine conformations with those of phenethylamines provided a tentative explanation for the alpha 2-adrenergic activity of the new imidazoles. A common binding mode for phenethylamines and imidazoles with alpha 2-adrenoceptors is proposed. Knowledge of the biological properties of the 4-substituted imidazoles, integrated with the information derived from computer-assisted molecular modeling, has provided new insights for the structural and conformational requirements of this class as new adrenergic drugs.

Publication types

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

MeSH terms

  • Adrenergic alpha-Agonists / chemical synthesis*
  • Adrenergic alpha-Agonists / chemistry
  • Adrenergic alpha-Agonists / pharmacology
  • Animals
  • Aorta / physiology
  • Cell Membrane / metabolism
  • Cerebral Cortex / metabolism
  • Crystallography, X-Ray
  • Drug Design*
  • Female
  • Humans
  • Imidazoles / chemistry*
  • Male
  • Medetomidine
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Muscle Contraction / drug effects
  • Naphthalenes / chemistry*
  • Platelet Aggregation Inhibitors / pharmacology
  • Rats
  • Receptors, Adrenergic, alpha / drug effects
  • Receptors, Adrenergic, alpha / metabolism
  • Structure-Activity Relationship


  • Adrenergic alpha-Agonists
  • Imidazoles
  • Naphthalenes
  • Platelet Aggregation Inhibitors
  • Receptors, Adrenergic, alpha
  • naphthalene
  • Medetomidine