In a broadened, interdisciplinary effort, using the combined capabilities of theoretical and synthetic chemistry, receptor pharmacology and animal testing, we plan to continue to (1) identify and calculate conformational and electronic properties of families of opiate narcotic analgesics, and understand the fundamental features of opiate-receptor interaction leading to agonism and antogonism, and (2) identify common features of diverse classes of chemical compounds leading to high affinity and activity at similar receptor sites. Specifically, the four primary aims during the proposed renewal period are: (1) Continue to test our hypotheses of the origin of agonist and antogonist activities in three classes of flexible opiates, by synthesis, receptor binding, and in vivo testing of promising 3- and 4-phenylpiperidines and opioid deptide analogs selected--as were those tested during the current period--from results of theoretical studies. (2) Calculate electronic properties, particularly electrostatic potential mapping for a) overlapping pharmacophores of diverse classes of opiates originally chosen on the basis of conformational properties alone and b) three classes of fused ring opiates in conjunction with receptor-binding studies: oxymorphones with N-substituent variation; oripavines with C7-tertiary alcohol substituent variation; and N-CH3 benzomorphans with C9Beta-alkanone variation for which conformational properties alone could not account for observed agonist/antagonist potency ratio variations. 3) Begin systematic studies of longer peptide opiates, particularly fragments of an substitution in Beta-endorphins, including theoretical, synthetic, and receptor-binding studies, to identify general conformational features that determine relative receptor affinity and analgesic activity. (4) Use of detailed receptor binding studies coupled with computer-assisted data analysis: a) to determine the molecular nature of the """"""""sodium effect"""""""" and its relevance to relative agonism and antagonism; b) to investigate the utility of naloxazone to identify proposed """"""""Mu1"""""""" analgesic receptors; and c) use kinetic experiments to investigate the validity of a recently proposed opiate receptor complex.
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