We have launched a broad program to study the relationship of opioid structure to biological function. Our general approach for computer aided drug design commences with the selection of target molecules based on molecular mechanics simulations. These molecules are then synthesized and characterized through troscopy, more extensive computer simulations and biological assays to develop structure/function relationships. As a result of prior work in this area, we have proposed a model, to explain the receptor selectivity of constrained opioids that we have designed and synthesized. Peptidomimetic modifications to the peptide backbone of enkephalin analogs allow us to test our conformational model of receptor selectivity. Specific target molecules are Tyr-c[D-gA2bu-mGly-rD-Phe- mLeu] and Tyr-c[D-gA2bu-mGly-gPhe-mLeu]. These represent a natural extension of our earlier work with retro-inverso modifications. The dipeptide analog 3-aminocyclopentane carboxylic acid (beta-Ac-'c) will be in enkephalin analogs. The follows our successful efforts in incorporating, 2 aminocyclopentane carboxylic acid (beta-Ac5c) in morphiceptin analogs to manipulate receptor specificity. challenge of discriminating among the four possible stereoisomers necessitate broad application of techniques such as NOESY, ROESY, extended COSY, and DISCO, as well as extensive computer simulations. Our past success in employing carrier conjugates of catecholamines to increase activity and specificity encourages similar experiments with enkephalins. Thus we propose to launch an integrated program for the sis and characterization of novel enkephalin conjugates. We have hopes of inducing not only receptor specific binding, but also of uncovering fundamental principles of membrane-peptide interaction. All final products emanating from our computer aided drug designs will be tested for biological activity. We have established collaborations with Dr. Peter Schiller at the Clinical Research Institute of Montreal for in vitro assays and Dr. Tony Yaksh here at UCSD for in vivo tests.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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University of California San Diego
Schools of Arts and Sciences
La Jolla
United States
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Yaksh, T L; Malmberg, A B; Ro, S et al. (1995) Characterization of the spinal antinociceptive activity of constrained peptidomimetic opioids. J Pharmacol Exp Ther 275:63-72
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