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      BP 897, a selective dopamine D3 receptor ligand with therapeutic potential for the treatment of cocaine-addiction.

      1 ,
      CNS drug reviews

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          Abstract

          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-alpha(1) (K(i) = 60 nM) and -alpha(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 GTPgammaS 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 microg/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.

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          Most cited references77

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              Roy Wise (1996)
              Addictive drugs have habit-forming actions that can be localized to a variety of brain regions. Recent advances in our understanding of the chemical 'trigger zones' in which individual drugs of abuse initiate their habit-forming actions have revealed that such disparate drugs as heroin, cocaine, nicotine, alcohol, phencyclidine, and cannabis activate common reward circuitry in the brain. Although these drugs have many actions that are distinct, their habit-forming actions (and perhaps the relevant elements of their disparate withdrawal symptoms) appear to have a common denominator, namely, similar effects in the brain mechanisms of reward.
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                Author and article information

                Journal
                CNS Drug Rev
                CNS drug reviews
                1080-563X
                1080-563X
                2003
                : 9
                : 2
                Affiliations
                [1 ] Department of Molecular Biology, Neuroscience Research, Abbott GmbH and Co. KG, P.O. Box 210805, D-67008 Ludwigshafen, Germany. francisco.javier.garcia-ladona@abbott.com
                Article
                12847556
                2a9aa7e0-389e-439f-9c7a-f0d8074388f3
                History

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