title: Effects of RGH-237 [N-{4-[4-(3-aminocarbonyl-phenyl)-piperazin-1-yl]-butyl}-4-bromo-benzamide], an orally active, selective dopamine D(3) receptor partial agonist in animal models of cocaine abuse.
abstract: Dopamine D(3) receptor partial agonism has been suggested as a potential therapeutic intervention in cocaine addiction. RGH-237 [N-{4-[4-(3-aminocarbonyl-phenyl)-piperazin-1-yl]-butyl}-4-bromo-benzamide] was identified as a novel selective dopamine D(3) receptor partial agonist and used for testing this hypothesis in animal models. The compound showed nanomolar affinity to human (K(i) = 6.7 nM) and rat (K(i) = 1.6 nM) D(3) receptors with an intrinsic activity of approximately 50%. It possessed several hundredfold selectivity over the D(2) receptor. The molecule bound with moderate (100-250 nM) affinity to 5-hydroxytryptamine 1A (5-HT(1A)) and nonselectively labeled opiate receptors. 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 h. RGH-237 at the oral dose of 10 mg/kg moderately but significantly inhibited the acquisition of cocaine-induced place preference, although by itself, it had no place-conditioning effect. The compound did not affect fixed ratio 1 cocaine self-administration. In a reinstatement paradigm of cocaine self-administration, the compound potently and dose-dependently blocked the cue-induced cocaine-seeking behavior 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. It did not exert notable effect on spontaneous motor activity of rats. Our results demonstrate that selective D(3) partial agonists may be an effective therapeutic means in the treatment of cocaine abuse.
authors.affiliation: Department of Behavioral Pharmacology, Gedeon Richter Plc., P.O. Box 27, Budapest, Hungary. i.gyertyan@richter.hu
authors.forename: István
authors.initials: I
authors.lastname: Gyertyán
authors.forename: Béla
authors.initials: B
authors.lastname: Kiss
authors.forename: Krisztina
authors.initials: K
authors.lastname: Gál
authors.forename: István
authors.initials: I
authors.lastname: Laszlovszky
authors.forename: Attila
authors.initials: A
authors.lastname: Horváth
authors.forename: Larisza I
authors.initials: LI
authors.lastname: Gémesi
authors.forename: Katalin
authors.initials: K
authors.lastname: Sághy
authors.forename: Gabriella
authors.initials: G
authors.lastname: Pásztor
authors.forename: Mária
authors.initials: M
authors.lastname: Zájer
authors.forename: Margit
authors.initials: M
authors.lastname: Kapás
authors.forename: Eva Agai
authors.initials: EA
authors.lastname: Csongor
authors.forename: György
authors.initials: G
authors.lastname: Domány
authors.forename: Károly
authors.initials: K
authors.lastname: Tihanyi
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Szombathelyi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001667:Binding, Competitive; D019970:Cocaine-Related Disorders / Q000188:drug therapy* / Q000378:metabolism; D003213:Conditioning, Psychological / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000819:agonists; D050637:Receptors, Dopamine D3 / Q000819:agonists*; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; C518644:N-(4-(4-(3-aminocarbonyl-phenyl)-piperazin-1-yl)-butyl)-4-bromo-benzamide; D010879:Piperazines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3