CONFORMATION-ACTIVITY RELATIONSHIPS OF CYCLIC DERMORPHIN ANALOGS

A theoretical conformational analysis (molecular mechanics study) of nine cyclic tetrapeptides, structurally related to the highly μ‐receptor‐selective dermorphin analogue , was performed. These compounds display considerable diversity in their μ‐receptor affinity and selectivity. A systematic search and subsequent energy minimization in absence of the exocyclic Tyr1 residue and Phe3 side chain revealed the constrained nature of the 11–13 membered ring structures contained in these analogues. No more than four low‐energy conformers (within 2 kcal/mol of the lowest energy conformation) were found in each case. After attachment of the Tyr1 moiety and Phe3 side chain to the “bare” low‐energy ring structures, a systematic search and energy minimization of these exocyclic moieties resulted in a limited number of low‐energy conformational families for all compounds. Five analogues with high μ‐receptor affinity— (Formula Presented.) , (A2 bu: alpha;, γ‐diaminobutyric acid) and (Formula Presented.) —all showed a tilted stacking interaction between the Tyr1 and Phe3 aromatic rings in the lowest or second lowest energy conformation found. The same kind of stacking was not possible in low‐energy conformers of the four analogues with poor affinity for the μ‐receptor (Formula Presented.) , : [Nα‐methylphenylalanine], and (Formula Presented.) It is concluded that a tilted stacking arrangement of the two aromatic rings may represent a structural requirement for high μ‐receptor affinity of the examined cyclic dermorphin analogues. Copyright © 1990 John Wiley & Sons, Inc.