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

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.