Despite intense research efforts directed toward the development of cocaine antagonists, compounds with significant cocaine antagonist activity have not been reported. Therefore, we believe that the discovery of a novel lead compounds of cocaine antagonists is currently a critical step. Toward this goal, we propose to use a novel approach, termed """"""""3D-database pharmacophore searching"""""""" to discover such compounds. The basic hypothesis of this proposal is that the cocaine recognition and dopamine (DA) binding sites, although possibly partially overlapping, are not identical. If this is true, it may be theoretically possible to discover molecules that will compete with cocaine at its binding site, but unlike cocaine, these molecules will not or only weakly inhibit the reuptake of DA. These molecules will thereby function as cocaine antagonists. Such compounds will be useful to counter some of the adverse effects of cocaine in cases of cocaine overdose or to help to maintain patients in cocaine treatment program.
The specific aims of this proposal are as follows: (1) Performance of molecular modeling studies of cocaine analogues and other DA transporter inhibitors to determine crucial structural features and their 3D geometric relationships that are important for their cocaine binding and DA reuptake activities; (2) Development of 3D pharmacophore models and search of a large 3D chemical database to identify compounds that meet pharmacophore requirements; (3) Performance of biological evaluations of selected compounds3 that meet the pharmacophore requirements in the [ H]mazindol binding and [3H]DA uptake assays. Compounds that show more than 5-fold selectivity in the [3H]DA reuptake and [3H]mazindol binding assays will be considered as cocaine antagonist lead compounds and will be further evaluated in assays of cocaine antagonism; (4) Performance of molecular modeling studies of these cocaine antagonist lead compounds and development of new pharmacophore models, and repetition of steps (2) and (3); (5) Further improvement of their potency and selectivity of these leads through molecular modeling-assisted, extensive chemical modifications. Our immediate goal is to discover novel lead compounds that may act as cocaine antagonists or """"""""partial agonists"""""""". Our preliminary results indicate that this is an achievable goal. Our ultimate goal is to further develop these lead compounds, through extensive chemical modifications, to arrive at potential clinical candidates for the treatment of cocaine dependence.
