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. 2007 Aug 13;569(1-2):70-6.
doi: 10.1016/j.ejphar.2007.04.054. Epub 2007 May 22.

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

Lance R McMahon  1 , Wouter Koek
Affiliations

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

Lance R McMahon et al. Eur J Pharmacol. .

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.

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Figures

Fig. 1
Fig. 1
Time course of hypothermia, catalepsy, and hypoactivity induced by different doses of Δ9-THC (left) and WIN 55212−2 (right). Abscissae: min expressed on log scale. Ordinates: mean (± S.E.M.) change in body temperature as ° C (top), catalepsy in s (middle), and activity counts (bottom).
Fig. 2
Fig. 2
Hypothermic effects of Δ9-THC (top) and WIN 55212−2 (bottom), and antagonism by SR 141716A and AM 251. Abscissae: dose in mg/kg body weight. Ordinate: mean (± S.E.M.) change in body temperature as ° C. Leftmost panels, effects of vehicle (VEH), alone or in combination with Δ9-THC and WIN 55212−2 (closed circles). Diamonds, effects of Δ9-THC (32 mg/kg) and WIN 55212−2 (10 mg/kg), alone or in combination with SR 141716A and AM 251. Open circles in rightmost panels, effects of antagonist alone. Values and dashed lines, ED50 values (agonists) and ID50 values (antagonists) in mg/kg.
Fig. 3
Fig. 3
Cataleptic effects of Δ9-THC (top) and WIN 55212−2 (bottom), and antagonism by SR 141716A and AM 251. Ordinate: mean (± S.E.M.) catalepsy in s. See Fig. 2 legend for other details.
Fig. 4
Fig. 4
Hypoactivity induced by Δ9-THC (top) and WIN 55212−2 (bottom), alone and in combination with SR 141716A and AM 251. Ordinate: mean (± S.E.M.) activity counts. See Fig. 2 legend for other details.
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