The strreochrmicul requirements for 6-opioid receptor binding q f a serie.r of linear pepti& antugoni.m with a novel conformationally restricted Phe analogue (Tic) as a second rcsiduluc wcw examined by using a variety qfcomputational chemistry methods. The 6-opioid receptor una-1ogue.s with significant aflinity, Tyr-Tic-NH, ( TI-NH2) , Tyr-Tic-Phe-OH (TIP), Tyr-Tic-Phe-NH2 (TIP-NH,), Tyr-Tic-Phe-Phe-OH (TIPP), Tyr-Tic-Phe-Phe-NH2) (TIPP-NH,), and thr low airinit y 6-opioid peptides Tyr-Pro-Phe-Pro-NH2 (morphicept in) and Tyr-Phe-Phe-Phe-NH, (TPPP-NH,), were included in this study. The conjbrmaiional prqfiles of these peptides were obtained by consecutive cycles of'high and low temperaturc molecular dynamic simulutions, coupled to molecular mechanical energy minimization carried out until no now conjhwztional minima were obtained. Comparing the resultsjbr TPPP-NH2 and TIPP-NH,, the presence of the confbrmationally restricted Tic residue did not greatly reduce [he number of unique low energy confivmations, but did allow low energy conformers involving cis bond.s between the fir.rt two residua. The conformational libraries of these peptidcs were examined.for their ability l o satisfy lhe three key ligand componcnts,for receptor recognition alreadv idiwtified by pri~vioi~.s studies ofhigh aifiinity cyclic ( Tyr'-rrPen2-Gly3-Phe4-o-Pen') enkephalin (DPDPE) type agonists: a protonated amine group, an aromatic ring, and a lipophilic moiety in a spec$c geometric arrangement. Two types of conformations common to the jive high 6-opioid affinity L-Tic analogues were found that satisfied these requirements, one with a cis and the other Mdth a trans peptide bond between the Tyr' and Tic2 residues. Moreover, both the Tic2 and Phe3 re.sidws could mimic the hydrophobic interactions with the receptor of the Phe4 moietjl in the cyclic DPDPE type agonists, consistent with the appreciable aflinity ofboth di-and tripeptides. The low 6-opioid receptor affinity qf morphiceptin can be understood as the result of conformational preferences that prevent the.fiC ,fillment ofthis pharmacophorejv recognition.