This application proposes to identify new selective dopamine D1 receptor agonists that compose potential candidates for use in treating cocaine addiction and other dopamine related illnesses. Both in silico and in vitro screens will be conducted against the D1 receptor as well as seven other functionally and structurally related receptors, namely, dopamine D2; serotonin 5HT2a; a-adrenergic 2a and 2b; b-adrenergic 1 and 2; and norepinephrine transporter. The choice of multiple receptors rather than the conventional single target approach is intended to minimize """"""""off-target"""""""" interactions early in the drug discovery process and to enhance the probability of identifying both potent and specific D1 agonists without or with much lower undesired side effects. In silico screening against chemical libraries will be based on a multiple targets based structure-activity relationship analysis. We have established an initial training dataset, consisting of the binding affinity values (Ki values) of 97 drug compounds in each of the eight receptors. Secondary chemical descriptor datasets associated with relevant biological activities will be obtained using a Recursive Partitioning algorithm. Compounds predicted via in silico screening to have potential D1 selective activity will be analyzed in in vitro and functional assay screens to confirm their actual vs. predicted binding affinities, selectivities and functionalities (i.e., agonist or antagonist).
Identified D1 agonist are useful as lead for further synthetic manipulations as anti-cocaine and or anti-Parkinson therapeutics. Intellectual property based on this information can either be licensed to pharmaceutical companies for further development into marketable therapeutics, or employed as a basis for collaborative relationships between Novascreen Biosciences Corporation and other firms.
