Executive Summary : | Objective: a. Design, synthesis and optimization of D1/D5 agonist and H3R specific antagonist b. Design & synthesis of lysine deacetylase inhibitors and activators of lysine acetyltransferase c. GPCR profiling of synthesized NCEs on above mentioned targets (D1/D5R, H3R)and selectivity profiling of Hits on panel of 20 GPCRs and determination hERG liability d. Determine the effect of GPCR hits on expression of dop-2 and dop-3, the C. elegansorthologs of human D1 and D2 receptors. e. Determine the effect of Hits on dopamine transporter, dopaminergic neurodegeneration and dopamine content employing transgenic C. elegans model. f. Cell based/ C.elegans based assays to screen for various synthetic/organic compounds which can enhance the histone acetylation mark/ enhance KAT activity g. DMPK properties, solubility, physicochemical parameters and parameters for CNS drug likeness (BBB penetration, logP, LLE etc) h. Determination of in vivo efficacy of best 3 leads (based on target affinity, selectivity and DMPK profile) in rodent models of cognitive impairments. 1. Follow-up of 2 best candidates in secondary models of transgenic/genetic models of Alzheimer's disease and neuronal ageing for efficacy. |