We will continue to pursue our primary goals of elucidating the structural and conformational features required of opioid ligands for binding with high affinity and high selectivity to specific opioid receptors and of using this information for the development of better (more potent, more selective, more stable, etc.) opioid analogs of potential therapeutic value. As in the past, our focus will be on the delta opioid receptor, however we propose to investigate an exciting initial lead that may help define important similarities and differences between delta and mu receptor requirements. Our general approach will combine analog design and synthesis, in vitro pharmacological testing, and conformational analysis. Two structural series, both containing analogs conformationally restricted by side chain to side chain cyclization via disulfide bonds, and both of which we have previously described will be investigated. The first of these is a pentapeptide series in which the lead compound is the highly delta selective DPDPE, while the second series is a further conformationally restricted tetrapeptide series, in which the lead analog JOM-13 (Tyr-D-Cys-Phe-D- Pen) also displays high delta selectivity. Analogs planned, most of which incorporate further conformational constraints, will identify specific structural and conformational features of the delta pharmacophore and will address the possibility that the two series may interact with different subsites of the delta receptor. Pharmacological screening of new analogs will be via assays for mu, delta, and kappa opioid receptor binding, to be done in our labs, and by standard MVD and GPI and smooth muscle bioassays, done via a Consortium arrangement with Prof. Frank Porreca of the University of Arizona. Conformational analyses will employ both experimental and computational methods. Modern NMR methods will be the primary experimental tool and will be complemented by distance geometry and molecular mechanics calculations. Our multidisciplinary, integrated approach provides us with all the tools necessary to pursue our goals in a reasonable and efficient manner.
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