title: Structure-activity studies of morphiceptin analogs: receptor binding and molecular determinants of mu-affinity and selectivity.
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, morphiceptin, 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- versus delta-receptor-binding sites and also indicate differences in mu-receptor affinity among them. The theoretical analyses allow identification of a preferred conformation leading 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.
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004723:Endorphins / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism*; D017450:Receptors, Opioid, mu; D013329:Structure-Activity Relationship
chemical_list: D004723:Endorphins; D008024:Ligands; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; C028889:morphiceptin