Design and synthesis of the CB1 selective cannabinoid antagonist AM281

R X Lan, Q Lu, P S Fan, J Gatley, N D Volkow, S R Fernando, Roger Guy Pertwee, A Makriyannis

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In the search for a radioligand capable of imaging cannabinoid CB1 receptors in the living human brain by SPECT (single photon emission computed tomography), N-(morpholin-4-yl)-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM281) was synthesized. This compound is an analog of the potent, CB1 receptor selective antagonist SR141716A [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide]. AM281 bound to brain and spleen membrane preparations (CB1 and CB2 receptors, respectively) with K-i values of 12 nM and 4200 nM, respectively. AM281 also inhibited the response of guinea-pig small intestine preparation to a cannabinoid receptor agonist. Thus, AM281 behaves as a CB1 receptor selective antagonist. Methods for the rapid, high-yield synthesis and purification of [I-123]AM281 were developed, and transaxially reconstructed brain SPECT images obtained after continuous infusion of [I-123]AM281 in baboons. Thus [I-123]AM281 may be suitable for imaging CB1 receptors in humans.

Original languageEnglish
Pages (from-to)39-45
Number of pages7
JournalAAPS PharmSci
Issue number2
Publication statusPublished - Jun 1999


  • AM281
  • cannabinoid CB1 receptor
  • cannabinoid receptor antagonist
  • CB1 selective ligand
  • SPECT image
  • I-123 LABELED AM251
  • SR 141716A
  • SR141716A
  • AM281
  • cannabinoid receptor antagonist
  • CB1 selective ligand

Cite this

Lan, R. X., Lu, Q., Fan, P. S., Gatley, J., Volkow, N. D., Fernando, S. R., Pertwee, R. G., & Makriyannis, A. (1999). Design and synthesis of the CB1 selective cannabinoid antagonist AM281. AAPS PharmSci, 1(2), 39-45.