BP 897

BP-897 Bioprojet

BP-897 is a dopamine D3 receptor agonist which is under development by Bioprojet for the potential treatment of drug craving and vulnerability to relapse that are elicited by drug-associated environmental stimuli; it is undergoing phase I trials [318397,334036,340721]. Preclinical investigations were carried out by Cambridge University and INSERM [295680]. BP-897 functions as a partial agonist in vitro and as either an agonist or an antagonist in vivo. It inhibits cocaine-seeking behavior that depends upon the presentation of drug-associated cues, without having any intrinsic, primary rewarding effects [334036]. In preclinical studies, BP-897 administration before testing reduced cocaine-seeking behavior in rats in a dose-dependent manner [304557,307758,334036]. In D3 receptor knockout mice, BP-897 has no effect [345710]. It does not reduce self-administration of cocaine in monkeys [318397].

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

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.

Effects of a dopamine D3 receptor ligand, BP 897, on acquisition and expression of food-, morphine-, and cocaine-induced conditioned place preference, and food-seeking behavior in rats

The present study addressed the role of dopaminergic D(3) receptors (D(3)R) in motivational processes in rats. The effects of the selective D(3)R partial agonist, BP 897 (0.25-1 mg/kg, i.p.), on the establishment and the expression of conditioned place preference (CPP) supported by food, morphine (4 mg/kg, s.c.), or cocaine (2 mg/kg, s.c.) were investigated using an unbiased, one-compartment, place-conditioning procedure. When administered alone, BP 897 (0.05-2 mg/kg, i.p.) did not support CPP; on the contrary, conditioned place avoidance (CPA) was observed at 1 mg/kg, suggesting that this dose of BP 897 could be perceived as aversive. When given before each cocaine injection during the conditioning phase, BP 897 (1 mg/kg) prevented the establishment of CPP, and a single administration of BP 897 (0.5 and 1 mg/kg) before the test session impaired the expression of cocaine CPP. In contrast, neither the establishment nor the expression of food- and morphine-CPP were significantly altered by BP 897 (up to 1 mg/kg), whereas the full but less selective D(3)/D(2)R agonists, 7-OH-DPAT (0.5-2 mug/kg, s.c.) and quinelorane (1 mug/kg, s.c.), prevented the acquisition of food CPP. In a within-session extinction schedule of lever pressing for food, BP 897 (0.06-2 mg/kg) was ineffective in potentiating response reinstatement induced by the noncontingent delivery of two food pellets, in contrast with quinelorane and 7-OH-DPAT where previous studies showed to be efficient in this respect (Duarte et al, 2003). These results indicate that BP 897 has no positive appetitive value on its own, and that a moderate degree of stimulation of D(3)R is not sufficient to modulate food-primed food-seeking behavior or alter incentive motivation for food, morphine, and/or their associated cues. However, D(3)R are likely involved in the perception of the rewarding value of cocaine and cocaine-paired cues. This suggests that the appetitive effects of cocaine are subserved by mechanisms different, at least in part, from those of morphine and food, and that D(3)R play a role only in the former.

The D3R partial agonist, BP 897, attenuates the discriminative stimulus effects of cocaine and D-amphetamine and is not self-administered

Growing attention has been directed towards the potential involvement of the dopamine D3 receptor (D3R) in modulating effects of psychomotor stimulants. BP 897 (N-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]-2-naphthylcarboxamide; aka BP 4.897 and DO897) is amongst the most selective partial agonists for the D3R receptor thus far reported. BP 897 was tested for its ability to support self-administration in rhesus monkeys (0.3-30 microg/kg) and for its ability to produce cocaine- and D-amphetamine-like discriminative stimulus effects in mice (0.01-17 mg/kg i.p.). BP 897 was not self-administered above vehicle and saline levels in any of the four monkeys tested, and produced less than 30% generalization from either the cocaine or D-amphetamine stimulus. When BP 897 was administered before administrations of cocaine or D-amphetamine, percent drug-lever selections were reduced. These results suggest that BP 897 has a profile of activity suitable for consideration as a potential treatment for cocaine dependency disorders.

The dopamine D3 receptor partial agonist, BP 897, is an antagonist at human dopamine D3 receptors and at rat somatodendritic dopamine D3 receptors

Recent studies have fueled the interest in dopamine D3 receptor antagonists and partial agonist for the treatment of psychosis and drug abuse, respectively. N-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]naphthalene-2-carboxamide (BP 897) is a dopamine D3 receptor selective ligand recently described as partial agonist with potential effects on drug-dependence. The aim of the present study was to determine both the functional activity of BP 897 at human dopamine D3 receptors expressed in Chinese hamster ovary (CHO) cells and in an electrophysiological in vivo model of dopaminergic activity. BP 897 failed to stimulate the human dopamine D3 receptor and showed antagonistic effects (cpIC(50)=9.51) in a [(35)S]GTPgammaS binding assay in cells expressing the human dopamine D3 receptor. In vivo, BP 897 up to 8.2 mg/kg, i.v., had no agonistic effects on firing rate of substantia nigra dopaminergic neurons and antagonized the quinpirole-induced inhibition of firing (DID(50)=1.1 mg/kg). Our data demonstrate that BP 897 acts, in vivo and in vitro, as a dopamine D3 receptor antagonist.