Open AccessBP 897, a Selective Dopamine D 3 Receptor Ligand with Therapeutic Potential for the Treatment of Cocaine‐Addiction
Author(s) -
GarciaLadona F. J.,
Cox B. F.
Publication year - 2003
Publication title -
cns drug reviews
Language(s) - English
Resource type - Journals
eISSN - 1527-3458
pISSN - 1080-563X
DOI - 10.1111/j.1527-3458.2003.tb00246.x
Subject(s) - dopamine , agonist , dopaminergic , substantia nigra , pharmacology , receptor , endocrinology , chemistry , gtpgammas , medicine , dopamine receptor , dopamine receptor d1 , endogenous agonist
BP 897 is a potent ( K i = 0.92 nM) dopamine D 3 receptor compound developed for the treatment of cocaine abuse and craving. BP 897 has a high selectivity for the dopamine D 3 versus D 2 receptors (70‐fold) and a moderate affinity for 5‐HT 1A receptors, ( K i = 84 nM), adrenergic‐α1 ( K i = 60 nM) and ‐α 2 adrenoceptors ( K i = 83 nM). BP 897 displays significant intrinsic activity at the human dopamine D 3 receptor by decreasing forskolin‐stimulated cAMP levels and by stimulating mitogenesis of dopamine D 3 ‐expressing NG108–15 cells. Although these findings suggest that BP 897 is a partial agonist, recent studies in Chinese Hamster Ovary (CHO) cells with expressed dopamine D 3 receptors demonstrated that BP 897 is devoid of any intrinsic activity but potently inhibits dopamine agonist effects (pIC 50 = 9.43 and 9.51) in agonist‐induced acidification rate or increase of GTPγS binding, respectively. In addition, BP 897 inhibits in vivo (EC 50 = 1.1 mg/kg, i.v.) agonist‐induced decrease of firing rate of dopaminergic neurons in the substantia nigra. It has been clearly shown that BP 897, 1 mg/kg, i.p., reduces cocaine‐seeking behavior in rats, without producing reinforcement on its own. In rhesus monkeys, BP 897 is not self‐administered (up to 30 μg/kg, i.v.) but reduces cocaine self‐administration. The potential usefulness of BP 897 in the treatment of drug‐seeking behavior is further supported by its effects in drug conditioning models. Although BP 897 reduces L‐DOPA‐induced dyskinesia in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐treated monkeys, it provokes a return of parkinsonian symptoms. At high doses BP 897 has been reported to produce catalepsy in rats. Pharmacokinetic and toxicological data have not yet been published. These interesting preclinical findings with BP 897 provide additional validation for dopamine D 3 receptor as a therapeutic target for the treatment of cocaine abuse and its associated central nervous system (CNS) disorders. BP 897 recently entered phase II clinical studies.