Synthesis and Pharmacological Evaluation of Potent and Highly Selective D₃ Receptor Ligands:  Inhibition of Cocaine-Seeking Behavior and the Role of Dopamine D₃/D₂ Receptors

Abstract

The synthesis, pharmacological evaluation, and structure-activity relationships (SARs) of a series of novel arylalkylpiperazines structurally related to BP897 (3) are described. In binding studies, the new derivatives were tested against a panel of dopamine, serotonin, and noradrenaline receptor subtypes. Focusing mainly on dopamine D(3) receptors, SAR studies brought to light a number of structural features required for high receptor affinity and selectivity. Several heteroaromatic systems were explored for their dopamine receptor affinities, and combinations of synthesis, biology, and molecular modeling, were used to identify novel structural leads for the development of potent and selective D(3) receptor ligands. Introduction of an indole ring linked to a dichlorophenylpiperazine system provided two of the most potent and selective ligands known to date (D(3) receptor affinity in the picomolar range). The intrinsic pharmacological properties of a subset of potent D(3) receptor ligands were also assessed in [(35)S]-GTPgammaS binding assays. Evidence from animal studies, in particular, has highlighted the dopaminergic system's role in how environmental stimuli induce drug-seeking behavior. We therefore tested two novel D(3) receptor partial agonists and a potent D(3)-selective antagonist in vivo for their effect in the cocaine-seeking behavior induced by reintroduction of cocaine-associated stimuli after a long period of abstinence, and without any further cocaine. Compound 5 g, a nonselective partial D(3) receptor agonist with a pharmacological profile similar to 3, and 5p, a potent and selective D(3) antagonist, reduced the number of active lever presses induced by reintroduction of cocaine-associated stimuli. However, 5q, a highly potent and selective D(3) partial agonist, did not have any effect on cocaine-seeking behavior. Although brain uptake studies are needed to establish whether the compounds achieve brain concentrations comparable to those active in vitro on the D(3) receptor, our experiments suggest that antagonism at D(2) receptors might significantly contribute to the reduction of cocaine craving by partial D(3) agonists.

Blockade of mesolimbic dopamine D3 receptors inhibits stress-induced reinstatement of cocaine-seeking in rats

“…Although evidence from the use of BP-897, a putative D 3 partial agonist, supports the involvement of D 3 receptors in cocaine's actions (Pilla et al 1999;see Preti 2001 for review), the exact role of D 3 receptors in drug reward as revealed by such studies remains elusive, as BP-897 may have more antagonist than partial agonist properties Wicke and Garcia-Ladona 2001). In addition, BP-897 also binds to other receptors such as D 2 , D 4 , 5-HT 1A , or α 1 receptors (Pilla et al 1999;Campiani et al 2003).…”

The role of central dopamine D3 receptors in drug addiction: a review of pharmacological evidence

“…A recent paper by Campiani et al [44] reported the pharmacological evaluation of a series of novel arylalkylpiperazine structures related to BP-897 as well as BP-897 itself. BP-897 (1 mg/kg) significantly reduced the number of active lever presses by male Sprague-Dawley rats following re-exposure to cocaine-associated stimuli.…”

The selective dopamine D3 receptor antagonists SB-277011A and NGB 2904 and the putative partial D3 receptor agonist BP-897 attenuate methamphetamine-enhanced brain stimulation reward in rats

“…However, growing evidence demonstrates that BP-897 may behave as a full antagonist at both DA D 2 (pK b =8.05) and D 3 (pK b =9.43) receptors Wicke and GarciaLadona 2001). Given that BP-897 has a 60-to 70-fold selectivity for human D 3 vs human D 2 receptors, and similar (60-to 70-fold) selectivity over other receptors such as α 1 -, α 2 -adrenergic receptors, and 5-HT 1A receptors (Pilla et al 1999;Campiani et al 2003), it is suggested that the aversive-like effects of BP-897 observed in the present study could be mediated by blockade of D 2 receptors or actions on other receptors. This is consistent with previous studies demonstrating that haloperidol (a preferential D 2 vs D 3 receptor antagonist) and raclopride (a mixed D 2 /D 3 receptor antagonist) have dysphorigenic or aversive properties in both humans and laboratory animals (Singh et al 1996;Kita et al 1999;Baldo et al 1999; see review by Platt et al 2002).…”