Pharmacological efficacy and safety profile of taranabant in preclinical species

Abstract

Taranabant is a highly selective and potent cannabinoid CB 1 receptor inverse agonist. We compared the pharmacological properties of taranabant with another inverse agonist, rimonabant, and determined the preclinical safety margins of taranabant. In vitro studies demonstrated that taranabant is $10-fold more potent than rimonabant at the CB 1 receptor, and taranabant is more selective based on offtarget in vitro screening. In vivo efficacy studies demonstrated that taranabant is $10-fold more potent than rimonabant in diet-induced obese rats. In repeat-dose toxicological studies, taranabant did not cause mortality in rodents and monkeys at exposure margins r6478 and 1922 times the estimated human exposure at 0.5 mg/day À1 . Taranabant did not produce CNS signs, including seizures, when administered to monkeys for 1 year at 10 mg/kg À1 day À1 (highest dose tested chronically), corresponding to an exposure margin of 974 times. In contrast to primates, taranabant produced brief handling-induced seizure-like activity in rodents, species predisposed to handling-induced seizures. Throughout the entire preclinical program, taranabant did not cause histopathological changes in the peripheral or central nervous system. In summary, the highly selective nature of taranabant is consistent with its generally favorable preclinical safety profile. Drug Dev Res 70 : 349-362, 2009. r

International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid Receptors and Their Ligands: Beyond CB1and CB2

“…Results obtained from equilibrium binding experiments with rat whole-brain membranes also suggest that ⌬ 9 -THC is a noncompetitive inhibitor of ligand binding to -and ␦-opioid receptors (IC 50 ϭ 7 and 16 M, respectively), although not to -opioid receptors or /phencyclidine receptors, and that inhibition of ligand binding to -opioid receptors can be induced by certain other cannabinoids (Vaysse et al, 1987). In addition, it has been found by both Fong et al (2009) (Lanzafame et al, 2004).…”

“…Taranabant, however, has been found to displace radiolabeled ligands from dopamine D 1 and D 3 receptors (K i ϭ 3.4 and 1.9 M, respectively) and from melatonin MT 1 receptors (K i ϭ 5.4 M) (Fong et al, 2007). In addition, both rimonabant (IC 50 ϭ 2 M) and taranabant (IC 50 ϭ 0.5 M) can induce radiolabeled ligand displacement from tachykinin NK 2 receptors (Fong et al, 2009).…”

“…In addition, evidence has been obtained, first, that at 10 M, both anandamide and 2-AG, but not AM251, R-(ϩ)-WIN55212, or CP55940 can act as allosteric inhibitors at the human adenosine A 3 receptor although not at the human adenosine A 1 receptor (Lane et al, 2010), and second, that both rimonabant (IC 50 ϭ 1.5 M) and taranabant (IC 50 ϭ 3.4 M) can induce radiolabeled ligand displacement from adenosine A 3 receptors (Fong et al, 2009). In contrast to taranabant (IC 50 Ͼ 10 M), rimonabant can also displace radiolabeled ligands from ␣ 2A -and ␣ 2C -adrenoceptors, from 5-HT 6 and angiotensin AT 1 receptors, and from prostanoid EP 4 , FP, and IP receptors with IC 50 values ranging from 2 to 7.2 M (Fong et al, 2009).…”

Rimonabant: a CB1 receptor antagonist as a direct interactional partner for μ- and δ-opioid receptor

“…Additionally in case of both radioligands rimonabant reached an IC 50 value in the micromolar range (Fig. 1C), similar to our previously reported data on CHO-MOR cell membranes (Zádor et al, 2012) and to other studies Fong et al, 2009;. Interestingly rimonabant also bound with an IC 50 in the micromolar range to other members of the GPCR family, such as adrenergic or 5-HT 6 receptors or to ion channels, like calcium, sodium and potassium channels (for review see .…”

“…It has been shown that it can affect the function of MOR through the CB 1 receptor (for review see Robledo et al, 2008), moreover there is an increasing number of studies reporting a direct effect of rimonabant on opioid receptors, mainly focusing on MORs Fong et al, 2009;Zádor et al, 2012). Recently our group also demonstrated an antagonistic character of rimonabant on MOR (Zádor et al, 2012) which was later affirmed by Seely and coworkers .…”