The long term goal of this component project of the PPG is to understand the molecular mechanisms of action of hallucinogenic drugs of abuse at a level of detail that will enable structure/based design and development of effective therapeutic methods of intervention. Because it continues a multi-disciplinary IRPG, , the proposed work profits from the fundamental understanding produced by its results. The focus is on computational modeling and stimulations of the discriminant receptor mechanisms of hallucinogens. They are integrated closely in the PPG with novel experimental work on the same systems in cells, and on the effects of hallucinogens in animal models incorporation the same receptor constructs, to address a continuum of questions connecting molecular structure with effects on animal behavior. The project provides a structural context for probing and understanding mechanisms of hallucinogens, in direct connection with experimental explorations and based on the common hypothesis that the hallucinogenic potential reflects specific structural elements responsible for distinct molecular mechanisms of ligand-receptor interaction. Hence,, the discriminant actions of hallucinogens addressed relate to 1) their models of interaction in human 5-HT2A and also 5-HT2C receptors, from binding to conformational rearrangements of the receptor that are involved in stabilization of the active status; and 2) the relation of any such distinctive conformational rearrangements due to the binding of hallucinogens to the selectivity and efficiency of G protein coupling. Powerful state-of-the-art approaches, a significant background of mechanistic understanding and molecular models, and a set of collaborative protocols tested successfully in ongoing work, underlies the studies aiming to 1: Reveal the specific role of various transmembrane segment 7 (TMS7) constructs in the dynamic mechanisms of receptor activation by hallucinogens; 2: Complete a computational analysis of differential effects of hallucinogens (compared to non-hallucinogenic congeners) on SM/FM based receptor activation by all structural motifs (SM) that constitute functional microdomains (FM); and 3: Determine from computational experiments the mode of binding of hallucinogens from an expanded list, and compare structurally cognitive non-hallucinogens. A common goal of all the studies: Translate conclusions reached from computational experiments into structure-based hypothesis about receptor constructs and ligands with defined activities, to correlate to findings on differential responses (Sealfon component) and to consider incorporation in whole animal studies (Hen component) of this PPG.
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