A proposal for the molecular basis of ? and ? opiate receptor differentiation based on modeling of two types of cyclic enkephalins and a narcotic alkaloid

Abstract

The molecular basis underlying the divergent receptor selectivity of two cyclic opioid peptides Tyr-c[N delta-D-Orn2-Gly-Phe-Leu-] (c-ORN) and [D-Pen2,L-Cys5]-enkephalinamide (c-PEN) was investigated using a molecular modeling approach. Ring closure and conformational searching procedures were used to determine low-energy cyclic backbone conformers. Following reinsertion of amino acid side chains, the narcotic alkaloid 7 alpha-[(1R)-1-methyl-1-hydroxy-3-phenylpropyl]-6-14-endoethenotetrahy dro oripavine (PEO) was used as a flexible template for bimolecular superpositions with each of the determined peptide ring conformers using the coplanarity and cocentricity of the phenolic rings as the minimum constraint. A vector space of PEO, accounting for all possible orientations for the C21-aromatic ring of PEO served as a geometrical locus for the aromatic ring of the Phe4 residue in the opioid peptides. Although a vast number of polypeptide conformations satisfied the criteria of the opiate pharmacophore, they could be grouped into three classes differing in magnitude and sign of the torsional angle values of the tyrosyl side chain. Only class III conformers for both c-ORN and c-PEN, having tyramine dihedral angles chi 1 = 150 degrees +/- 30 degrees and chi 2 = -155 degrees +/- 20 degrees, had significant structural and conformational properties that were mutually compatible while respecting the PEO vector space. Comparison of these properties in the context of the divergent receptor selectivity of the studied opioid peptides suggests that the increased distortion of the peptide backbone in the closure region of c-PEN together with the pendant beta,beta-dimethyl group, combine to generate a steric volume which is absent in c-ORN and that may be incompatible with a restrictive topography of the mu receptor. The nature and stereochemistry of substituents adjacent to the closure region of the peptides could also modulate receptor selection by interacting with a charged (delta) or neutral (mu) subsite.

S-p-methylbenzyl-β-phenylcysteine: a potential tool for probing receptor topologies

“…In order to demonstrate the potential interest in using the P-phenylcysteine residue in the context of probing receptor sites, we have incorporated this particular residue with its predicted most stable conformation into a potential opiate ligand. This simulation is to be related to our preceding paper 29 on the search for the active conformation of the 6 selective opiate Tyr-D-Pen-Gly-Phe-Cys-NH,. The cysteine adopts a D backbone conformation and x1 and x2 were both trans which is compatible with the preferred conformation of an erythro-phenyl-L-cysteine (see Table 1).…”

Insertion of the methylene-oxy surrogate of the amide bond into Boc-Val-Leu-OH: X-ray crystal structure, solution conformation and molecular modelling study

“…van der Waals radius served to reject conformations with bad atomic contact. 18 For each allowed conformation, the conformational energy was computed. This energy was calculated using the molecular mechanic approach using the standard parameters of the Tripos force field.…”