STRUCTURE-ACTIVITY STUDIES OF MORPHICEPTIN ANALOGS - RECEPTOR-BINDING AND MOLECULAR DETERMINANTS OF MU-AFFINITY AND SELECTIVITY

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Abstract
In this study we report the systematic investigation of conformational profiles and electronic properties of a series of analogs of the .MU.-selective opioid peptide, mnorphiceptin, together with receptor-binding studies of some of these analogs. In particular, we have investigated the effect of: substitution in the second position, substitution of D-Pro for L-Pro in the second and fourth positions, the addition of an N-methyl group at the third position, and variations in the carboxyl end group. The binding studies confirm the preference of these analogs for .mu.-verus .delta.-receptor-binding sites and also indicate differences in .mu.-receptor affinity among them. The theoretical analyses allow identification of a preferred conformation lending to high .mu.-receptor affinity and two reliable indicators of relative .mu.-receptor affinities. These properties are the energy required to obtain the candidate .mu.-binding conformer and the extent to which each compound overlaps with the highest affinity compound in this conformation. In addition, electronic interactions deleterious to high affinity .mu.-binding are identified.