Locomotor activity and occupancy of brain cannabinoid CB1 receptors by the antagonist/inverse agonist AM281

Abstract

The goals of this study were to examine the relationship between intravenous doses of the cannabinoid CB1 receptor antagonist AM281 (N‐(morpholin‐4‐yl)‐5‐(4‐iodophenyl)‐1‐(2,4‐dichlorophenyl)‐4‐methyl‐1H‐pyrazole‐3‐carboxamide) and the degree of occupancy of this receptor, and to relate occupancy to the ability of this compound to antagonize the sedative effects of the cannabinoid receptor agonist WIN 55,212‐2. Occupancy was determined by measuring the ability of intravenous doses of AM281 to inhibit in vivo binding of [131I]AM281 in brain areas, and locomotor activity was assessed by measuring the rate of beam crossings in a photocell apparatus. As previously documented, WIN 55,212‐2 (1 mg/kg, i.v.) significantly reduced locomotor activity at early times after administration. Co‐injection of AM281 (0.3 mg/kg i/v) and WIN 55,212‐2 restored the rate of beam crossings to that seen on injection of vehicle. In addition, AM281 (0.3 mg/kg i/v) approximately doubled locomotor activity between 60–120 min when injected alone. The IC50 value for displacement of [131I]AM281 by AM281 was 0.45 mg/kg. These observations confirm earlier indications that AM281 is a CB1 receptor antagonist or inverse agonist and suggest the existence of an endogenous cannabinoid tone that moderates exploratory locomotor activity. Synapse 38:477–482, 2000. © 2000 Wiley‐Liss, Inc.

The relationship of in vivo central CB1 receptor occupancy to changes in cortical monoamine release and feeding elicited by CB1 receptor antagonists in rats

“…While occupancy measurements have previously been reported using [ 131 I]AM281 (Cosenza et al 2000), we have described here a more advantageous in vivo central CB 1 receptor occupancy method, this one using commercially available [ 3 H]SR141716A. Employing this method, we demonstrated that SR141716A and SLV319 occupy cortical CB 1 receptors consistently between 1 and 3 h after dosing.…”

“…The occupancy method described here offers certain methodological advances compared to the study by Cosenza et al (2000). Specifically, in the latter study, the nonspecific binding was estimated using an area thought to contain very low or no CB 1 receptor density, the brain stem.…”

“…Although others have measured in vivo CB 1 receptor occupancy with a derivative of SR141716A, [ 131 I]AM281, relating this occupancy to changes in locomotor activity (Cosenza et al 2000), we sought to evaluate central CB 1 receptor occupancy using [ 3 H]SR141716A in relation to physiological and neurochemical changes elicited by leading CB 1 receptor antagonists that are directly relevant to their therapeutic potential in the clinic. Specifically, dose-occupancy curves were generated for two orally administered CB 1 receptor antagonists, SR141716A and SLV319 ((4S)-(-)-3-(4-chlorophenyl)-N-methyl-N'-[(4-chlorophenyl)sulfonyl] -4-phenyl-4,5-dihydro -1H-pyrazole-1-carboxamidine) (Lange et al 2004).…”

The PET Radioligand [11C]MePPEP Binds Reversibly and with High Specific Signal to Cannabinoid CB1 Receptors in Nonhuman Primate Brain

“…These two deficiencies apply to most radiotracers developed to date for the CB 1 receptor. These ligands have been based on the structures of rimonabant (Cosenza et al, 2000;Gatley et al, 1996;Horti et al, 2006;Katoch-Rouse et al, 2003;Mathews et al, 2000Mathews et al, , 2002, cannabinoids (Charalambous et al, 1991), and alkylindoles (Gifford et al, 2002;Tamagan et al, 1999). In contrast to these older agents, 11 C-JHU75528 is a notable exception (see 'Discussion') and has moderate brain uptake and specific signal (Horti et al, 2006).…”

In Vitro Metabolism of Diarylpyrazoles, a Novel Group of Cannabinoid Receptor Ligands

“…Two less potent CB 1 -selective analogs, AM251 and AM281 ( Fig. 1), have also been reported (Gatley et al, 1997(Gatley et al, , 1998Lan et al, 1999;Cosenza et al, 2000). It is believed that the antagonistic activity of the diarylpyrazoles is attributable to the structural properties of 1-and 5-substituents, whereas the 3-substituent appears to be involved in agonism and receptor activation (Wiley et al, 2001).…”