SR147778 [5-(4-Bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide], a New Potent and Selective Antagonist of the CB1 Cannabinoid Receptor: Biochemical and Pharmacological Characterization

Abstract

Based on binding, functional, and pharmacological data, this study introduces SR147778 [5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(1-piperidinyl)-1H-pyrazole-3-carboxamide] as a highly potent, selective, and orally active antagonist for the CB1 receptor. This compound displays nanomolar affinity (K i ϭ 0.56 and 3.5 nM) for both the rat brain and human CB1 recombinant receptors, respectively. It has low affinity (K i ϭ 400 nM) for both the rat spleen and human CB2 receptors. Furthermore, it shows no affinity for any of the over 100 targets investigated (IC 50 Ͼ 1 M). In vitro, SR147778 antagonizes the inhibitory effects of CP 55,940 [(1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol] on both the mouse vas deferens contractions (pA 2 value ϭ 8.1) and on forskolin-stimulated adenylyl cyclase activity in the U373 MG cell lines (pA 2 value ϭ 8.2) but not in Chinese hamster ovary (CHO) cells permanently expressing the human peripheral cannabinoid receptor (hCB2). SR147778 is able to block the mitogen-activated protein kinase activity induced by CP 55,940 in the CHO cell line expressing human brain cannabinoid receptor (IC 50 ϭ 9.6 nM) but was inactive in cells expressing hCB2. After oral administration, SR147778 displaced the ex vivo [3 H]-CP 55,940 binding to mouse brain membranes (ED 50 ϭ 3.8 mg/ kg) with a long duration of action, whereas it did not interact with the CB2 receptor expressed in the mouse spleen. Using different routes of administration, SR147778 (0.3-3 mg/kg) is shown to antagonize pharmacological effects (hypothermia, analgesia, and gastrointestinal transit) induced by R-(ϩ)-(2,3-dihydro-5-methyl-3-[{4-morpholinyl}methyl] pyrol [1,2,3-de]-1,4-benzoxazin-6-yl)(1-naphthalenyl) methanone in mice. Finally, per se, SR147778 (0.3-10 mg/kg) is able to reduce ethanol or sucrose consumption in mice and rats and food intake in fasted and nondeprived rats.Marijuana (Cannabis sativa L.) has been used for many centuries as a recreational drug or as a therapeutic agent. It is now well established that tetrahydrocannabinol (⌬ 9 -THC), the main active component of marijuana, the endocannabinoids (Devane et al., 1992;Mechoulam et al., 1995) as well as synthetic cannabinoid receptor agonists mediate their cellular effects through specific cannabinoid receptors, members of the G-protein-coupled receptor super family. To date, two cannabinoid receptors have been identified, CB1 (Matsuda et al., 1990; Gé rard et al., 1991) and CB2 (Munro et al., 1993). CB1 is predominantly expressed in the brain (Westlake et al., 1994) but also in some peripheral tissues (Gé rard et al., 1991;Bouaboula et al., 1993;Shire et al., 1995). The CB2 subtype is found mainly in immune cells (Munro et al., 1993; Galiè gue et al., 1995) but also in rat microglial cells (Walter et al., 2003). Both Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.104.067884.ABBREVIATIONS: ⌬ 9 -THC, tetrahydrocannabinol; SR147778, 5-(4-bromop...

The cannabinoid receptor agonist WIN 55,212-2 facilitates the extinction of contextual fear memory and spatial memory in rats

“…Consequently, the genetic deletion of CB1 cannabinoid receptors results in a strong impairment of short-term and long-term extinction of conditioned fear, which was confirmed by the use of rimonabant, a selective CB1 cannabinoid receptor antagonist. The recent availability of SR 147778 (SR), a newly developed antagonist with high affinity and specificity for CB1 cannabinoid receptors (Rinaldi-Carmona et al 2004), leads to the possibility of confirming and extending these previous findings observed with rimonabant (Rinaldi-Carmona et al 1995). Moreover, in light of the fact that fear memories become increasingly resistant to extinction with age (Suzuki et al 2004), it seems to be of interest to investigate whether the cannabinoid system may influence extinction of remote fear memories as well.…”

The Endocannabinoid System: A Promising Target for the Management of Type 2 Diabetes

“…Some of these compounds have been identified as being actively pursued in the biopharmaceutical industry as leads for the pharmacotherapy of obesity and related metabolic disorders, including type 2 diabetes (table 1) [16]. In general, such lead selective CB1 receptor antagonists for weight-management have 8 demonstrated acute preclinical activity in reducing food intake and body weight, and longer-term efficacy with chronic feeding in non-obese rodents and standard dietary and genetic obesity models [70][71][72][73][74][75][76][77]. Measurements of energy expenditure, adipose tissue mass and distribution and metabolic parameters (e.g., plasma glucose and insulin levels, lipids) have also been routine components of the lead evaluation process.…”

Cortico-limbic circuitry for conditioned nicotine-seeking behavior in rats involves endocannabinoid signaling

“…Blockade of cannabinoid CB1 receptors with selective antagonists, such as rimonabant or SR147778, reduces oral ethanol intake in a two-bottle choice paradigm and ethanol self-administration using operant procedure (Arnone et al 1997;Rinaldi-Carmona et al 2004;Cippitelli et al 2005;Gessa et al 2005;Economidou et al 2006). Rimonabant also decreases nicotine (Cohen et al 2002(Cohen et al , 2005bLe Foll and Goldberg 2004;Forget et al 2005) and opiate (Chaperon et al 1998;De Vries et al 2003) selfadministration, place preference, and cue-induced drugseeking behavior in laboratory animals.…”