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Differences in the relative potency of SR 141716A and AM 251 as antagonists of various in vivo effects of cannabinoid agonists in C57BL/6J mice.
Eur J Pharmacol. 2007 Aug 13; 569(1-2):70-6.EJ

Abstract

Although the cannabinoid CB(1) antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR 141716A) blocks many of the in vivo effects of cannabinoids, the antagonist activity of SR 141716A is limited under some conditions. The general aims of this study were to: 1) examine whether the limited antagonist activity of SR 141716A generalizes to the cannabinoid CB(1) antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM 251); and 2) examine mechanisms by which cannabinoids produce hypothermia, catalepsy, and hypoactivity in C57BL/6J mice. SR 141716A and AM 251 were administered alone and in combination with the cannabinoid agonists triangle up(9)-tetrahydrocannabinol (triangle up(9)-THC) and R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)-methyl]pyrrolol-[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone (WIN 55212-2). triangle up(9)-THC and WIN 55212-2 produced catalepsy, hypothermia, and hypoactivity with similar potency; WIN 55212-2 produced greater hypothermia than triangle up(9)-THC, otherwise differences in maximal effect were not detected in the other assays. When administered alone, the antagonists did not produce catalepsy or alter body temperature and they decreased locomotor activity. SR 1417167A and AM 251 blocked catalepsy and hypothermia, and partially attenuated hypoactivity, produced by triangle up(9)-THC and WIN 55212-2. While the antagonists were equipotent in blocking agonist-induced hypothermia, SR 141716A was 6-fold more potent than AM 251 in blocking agonist-induced catalepsy. The results demonstrate that SR 141716A and AM 251 have strikingly similar behavioral activity, i.e., they block some and not other in vivo effects of cannabinoid agonists, and further demonstrate differences in the maximum effect of cannabinoid agonists that might be related to differences in agonist efficacy. While the results strongly suggest that cannabinoid CB(1) receptors mediate the hypothermic and cataleptic effects of cannabinoids, differences in the relative potency of antagonists suggest that mechanisms responsible for these effects are not identical.

Authors+Show Affiliations

Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. mcmahonl@uthscsa.eduNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

17553486

Citation

McMahon, Lance R., and Wouter Koek. "Differences in the Relative Potency of SR 141716A and AM 251 as Antagonists of Various in Vivo Effects of Cannabinoid Agonists in C57BL/6J Mice." European Journal of Pharmacology, vol. 569, no. 1-2, 2007, pp. 70-6.
McMahon LR, Koek W. Differences in the relative potency of SR 141716A and AM 251 as antagonists of various in vivo effects of cannabinoid agonists in C57BL/6J mice. Eur J Pharmacol. 2007;569(1-2):70-6.
McMahon, L. R., & Koek, W. (2007). Differences in the relative potency of SR 141716A and AM 251 as antagonists of various in vivo effects of cannabinoid agonists in C57BL/6J mice. European Journal of Pharmacology, 569(1-2), 70-6.
McMahon LR, Koek W. Differences in the Relative Potency of SR 141716A and AM 251 as Antagonists of Various in Vivo Effects of Cannabinoid Agonists in C57BL/6J Mice. Eur J Pharmacol. 2007 Aug 13;569(1-2):70-6. PubMed PMID: 17553486.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differences in the relative potency of SR 141716A and AM 251 as antagonists of various in vivo effects of cannabinoid agonists in C57BL/6J mice. AU - McMahon,Lance R, AU - Koek,Wouter, Y1 - 2007/05/22/ PY - 2007/01/03/received PY - 2007/04/11/revised PY - 2007/04/25/accepted PY - 2007/6/8/pubmed PY - 2007/10/27/medline PY - 2007/6/8/entrez SP - 70 EP - 6 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 569 IS - 1-2 N2 - Although the cannabinoid CB(1) antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR 141716A) blocks many of the in vivo effects of cannabinoids, the antagonist activity of SR 141716A is limited under some conditions. The general aims of this study were to: 1) examine whether the limited antagonist activity of SR 141716A generalizes to the cannabinoid CB(1) antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM 251); and 2) examine mechanisms by which cannabinoids produce hypothermia, catalepsy, and hypoactivity in C57BL/6J mice. SR 141716A and AM 251 were administered alone and in combination with the cannabinoid agonists triangle up(9)-tetrahydrocannabinol (triangle up(9)-THC) and R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)-methyl]pyrrolol-[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone (WIN 55212-2). triangle up(9)-THC and WIN 55212-2 produced catalepsy, hypothermia, and hypoactivity with similar potency; WIN 55212-2 produced greater hypothermia than triangle up(9)-THC, otherwise differences in maximal effect were not detected in the other assays. When administered alone, the antagonists did not produce catalepsy or alter body temperature and they decreased locomotor activity. SR 1417167A and AM 251 blocked catalepsy and hypothermia, and partially attenuated hypoactivity, produced by triangle up(9)-THC and WIN 55212-2. While the antagonists were equipotent in blocking agonist-induced hypothermia, SR 141716A was 6-fold more potent than AM 251 in blocking agonist-induced catalepsy. The results demonstrate that SR 141716A and AM 251 have strikingly similar behavioral activity, i.e., they block some and not other in vivo effects of cannabinoid agonists, and further demonstrate differences in the maximum effect of cannabinoid agonists that might be related to differences in agonist efficacy. While the results strongly suggest that cannabinoid CB(1) receptors mediate the hypothermic and cataleptic effects of cannabinoids, differences in the relative potency of antagonists suggest that mechanisms responsible for these effects are not identical. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/17553486/Differences_in_the_relative_potency_of_SR_141716A_and_AM_251_as_antagonists_of_various_in_vivo_effects_of_cannabinoid_agonists_in_C57BL/6J_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(07)00534-1 DB - PRIME DP - Unbound Medicine ER -