Received for publication May 18, 2006.
Revised December 13, 2006.
Accepted for publication December 14, 2006.

Effects of RGH-237 (N-{4-[4-(3-aminocarbonyl-phenyl)-piperazin-1-yl]-butyl}-4-bromo-benzamide), an orally active, selective dopamine D₃ receptor partial agonist in animal models of cocaine abuse

Abstract

RGH-237 (N-{4-[4-(3-aminocarbonyl-phenyl)-piperazin-1-yl]-butyl}-4-bromo-benzamide) is a novel potent and selective dopamine D₃ receptor partial agonist compound. It showed nanomolar affinity to both human (K_i=6.7 nmol/l) and rat (K_i=1.6 nmol/l) D₃ receptors with an intrinsic activity of appr. 50 %. It possessed several hundred-fold selectivity over the D₂ receptor. The compound bound with moderate affinity to human and rat 5-HT_1A receptors (K_i=136 and 245 nmol/l, respectively) and to non-selectively labelled populations of rat opiate receptors (K_i=129 nmol/l). RGH-237 proved to be practically inactive on more than 40 other targets including monoaminergic, cholinergic, GABAergic and glutamatergic receptors. In rats orally administered RGH-237 was well and rapidly absorbed yielding 41 % oral bioavailability. At its pharmacologically active dose (10 mg/kg p.o.) the brain concentration of RGH-237 reached 110 ng/g. Its blood and brain levels were sustained for 3 hours. RGH-237, at the oral dose of 10 mg/kg but not 30 mg/kg moderately though significantly inhibited the acquisition of cocaine-induced place-preference, while itself had no place-conditioning effect. The compound did not affect FR1 cocaine self-administration. In a reinstatement paradigm of cocaine self-administration the compound potently and dose-dependently blocked the cue-induced cocaine-seeking behaviour of rats at 10 and 30 mg/kg oral doses. RGH-237 did not affect seeking activity for natural rewards such as sucrose and water. The molecule did not exert notable effect on spontaneous motor activity of rats. The above properties render RGH-237 a useful pharmacological tool for investigating the therapeutic potential of dopamine D₃ partial agonism in animal models of cocaine addiction.

Key words: RGH-237, brain level, cocaine place-preference, cocaine self-administration, dopamine D₃ partial agonist, reinstatement of cocaine seeking