Structure-activity relationships of pyrazole derivatives as cannabinoid receptor antagonists

J Med Chem. 1999 Feb 25;42(4):769-76. doi: 10.1021/jm980363y.


As a potent, specific antagonist for the brain cannabinoid receptor (CB1), the biarylpyrazole N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A; 1) was the lead compound for initiating studies designed to examine the structure-activity relationships of related compounds and to search for more selective and potent cannabimimetic ligands. A series of pyrazole derivatives was designed and synthesized to aid in the characterization of the cannabinoid receptor binding sites and also to serve as potentially useful pharmacological probes. Therapeutically, such compounds may have the ability to antagonize harmful side effects of cannabinoids and cannabimimetic agents. Structural requirements for potent and selective brain cannabinoid CB1 receptor antagonistic activity included (a) a para-substituted phenyl ring at the 5-position, (b) a carboxamido group at the 3-position, and (c) a 2,4-dichlorophenyl substituent at the 1-position of the pyrazole ring. The most potent compound of this series contained a p-iodophenyl group at the 5-position, a piperidinyl carboxamide at the 3-position, and a 2,4-dichlorophenyl group at the 1-position of the pyrazole ring. The iodinated nature of this compound offers additional utility as a gamma-enriching SPECT (single photon emission computed tomography) ligand that may be useful in characterizing brain CB1 receptor binding in vivo.

Publication types

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

MeSH terms

  • Animals
  • Cannabinoids / metabolism*
  • Guinea Pigs
  • Humans
  • In Vitro Techniques
  • Intestine, Small / drug effects
  • Intestine, Small / innervation
  • Male
  • Mice
  • Muscle Contraction / drug effects
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / physiology
  • Myenteric Plexus / drug effects
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / metabolism
  • Piperidines / pharmacology
  • Prosencephalon / drug effects
  • Prosencephalon / metabolism
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / chemistry
  • Pyrazoles / metabolism
  • Pyrazoles / pharmacology
  • Rats
  • Receptors, Cannabinoid
  • Receptors, Drug / antagonists & inhibitors*
  • Spleen / drug effects
  • Spleen / metabolism
  • Structure-Activity Relationship
  • Vas Deferens / drug effects
  • Vas Deferens / physiology


  • Cannabinoids
  • Piperidines
  • Pyrazoles
  • Receptors, Cannabinoid
  • Receptors, Drug
  • AM 251