SYNTHESIS AND DESIGN OF NOVEL SELECTIVE DOPAMINE D3 RECEPTOR MODULATORS FOR THE TREATMENT OF COCAINE ADDICTION

Abstract

A number of research teams have published on the biological effects of cocaine. In humans, cocaine blocks dopamine transporters and reduces dopamine receptor expression in the neuron synapses. The D2 antagonists, sulpiride and eticlopride, for example, inhibited the cocaine-induced place preference conditioning in preweanling rats.[1] However, several clinical studies reported that some marketed D2 antagonists can cause Parkinson-like extrapyramidal side effects when D2 receptor occupancy in the brain is over 80%.[2] To mitigate the risk of this side effect, scientists have been exploring a variety of neurobiological targets as alternatives of D2 receptors. In 1990, the dopamine D3 receptor was discovered by Sokoloff et al.[3] It has been demonstrated to be a therapeutic target for the treatment of neurological, psychiatric symptoms, schizophrenia, drug addiction, pain relief and Parkinson's disease.[4] In 1999,[5] Pilla et al. reported the first D3 partial agonist, BP-897 (Table 1.2.3) as a possible treatment for cocaine addiction. They claimed that BP-897 conferred a "buffering" capacity to neutralize excess dopamine release level and to maintain a moderate degree of dopamine stimulation, giving an effective restoring treatment for a cocaine-induced reward process. A BP-897 analog, LS-4-132 (Figure 2.2b), developed by Mach, et. al. University of Pennsylvania possesses high affinity (Ki = 0.2 nM) and high selectivity (LS-4-132: D2/D3 = 193 versus BP-897: D2/D3 = 68) for the D3 receptor. However, it has low solubility and is not metabolically stable enough to support in vivo efficacy assays. Therefore, this work is focused on the design of new generations of compounds with improved ADME properties, while maintaining D3 binding affinity and D3 receptor selectivity. The structure scaffold (Figure 2.2a) used for this program can be divided into four regions, 1) aryl moiety 1, 2) the amide region, 3) the linker, and 4) the piperazine substituent region. To accomplish this task, each region was modified, in some cases using bioisosteres, in accordance with medicinal chemistry methodologies to generate structure-activity relationship (SAR) data. The initial SAR began with an investigation of the piperazine region via a fragment-based strategy. More than 60 analogs were prepared and assessed for D3 binding affinity. The substituents of potent ligands were then incorporated into target compound scaffolds. In addition to the modification of the piperazine region, aryl moiety 1, the amide region, and linker region were modified by installing hetero-atom into the linkers, inverting the amide, and replacing the phenyl ring of aryl moiety 1 with various heteroaryl-moieties. These modifications were designed to improve compound solubility. Replacing the butyl linker with hetero-atom linkers did indeed improve solubility, but these compounds had short half-lives. Interestingly, replacement of amide region with inverse amide extended microsomal stability. Based on this observation, the inverse amide was employed into additional scaffolds. At the same time, heteroaryl groups are used to replace aryl moiety 1 to generate new compounds. Some of these compounds were identified as potent and selective D3 ligands, and improvements in microsomal half-lives supported assessment in rat in vivo PK models. Four compounds identified to date were examined in this model and found to have sufficient in vivo exposure for advancement to in vivo efficacy screening in a collaborator laboratory.