Executive Summary : | Objective: Design, synthesis and optimization of KOR antagonist and biased agonis . Design, synthesis and optimization of Nav 1.7 and TRPV 1 antagonist .GPCR profiling (KOR) and selectivity screening (KOR vs MOR & DOR) and biased score for agonist . Activity profiling against of Nav 1.7 and TRPV 1 . Optimization of leads based on DMPK properties, physicochemical parameters and parameters for CNS drug likeness (BBB penetration, logP, LLE etc). Establishment of efficacy in secondary in vivo models of TRD and neuropathic pain as per the decision tree. Identification of Leads for follow-up project regarding preclinical safety and toxicity studies. . Design, synthesis and optimization of KOR antagonist and biased agonist . GPCR profiling (KOR) and selectivity screening (KOR vs MOR & DOR) and biased score for agonist . Optimization of leads based on DMPK properties, physicochemical parameters and parameters for CNS drug likeness (BBB penetration, logP, LLE etc. Establishment of efficacy in secondary in vivo models of TRD and neuropathic pain as per the decision tree. Identification of Leads for follow-up project regarding preclinical safety and toxicity studies. 1) Design and synthesis of novel BBB penetrating peptides and peptidomimetic modulators of TRPV1 and Nav 1.7 .Using BBB permeable vectors as a carrier of newly designed and known compounds .Biodegradable nanoparticle conjugates to deliver these modulators into the brain . In vitro screening of NCEs for novel antagonists of Nav1 .7 and TRPV1 . Determine the in vivo efficacy of novel Nav1. 7 or TRPV1 antagonist in rat model of neuropathic pain. |