Development of a model for the delta-opioid receptor pharmacophore .2. conformationally restricted phe(3) replacements in the cyclic delta-receptor selective tetrapeptide tyr-c[d-cys-phe-d-pen]oh (jom-13)
The in vitro pharmacological properties and conformational features of analogs of the delta opioid receptor selective tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13) in which the Phe(3) residue was replaced by each of the four stereoisomers of beta-methylphenylalanine (beta-MePhe) were investigated. Both analogs in which the a carbon of the Phe(3) replacement has L-stereochemistry display high affinity for delta receptors with the (2S,3S)-MePhe(3) analog exhibiting approximately 8-fold higher affinity than the (2S,3R)-MePhe(3) diastereomer. Surprisingly, one analog with D-stereochemistry in residue 3, the (2R,3R)-MePhe(3) analog, also displays high affinity for the delta receptor and is extraordinarily selective for this receptor. All analogs were agonists in the mouse vas deferens(MVD) and guinea pig ileum (GPI) smooth muscle bioassays; displaying MVD and GPI potencies consistent with their delta and mu opioid receptor affinities, respectively. The use of beta-MePhe as a replacement for Phe(3) was based upon the desire to reduce the conformational flexibility of the Phe(3) side chain by imposing a steric rotational constraint in the form of the beta-methyl substituent and to thus deduce the residue 3 side chain orientation in the delta receptor-bound conformation from the correlation between delta receptor binding affinities and conformational preferences. Molecular mechanics computations revealed, however, that the conformational constraints imposed by the beta-methyl group in the (2S,3S)-MePhe(3) and (2S,3R)-MePhe(3) analogs were too modest to allow unequivocal determination of delta receptor-bound residue 3 side chain conformation. However, analysis of the high-affinity (2R,3R)-MePhe(3) analog revealed a strong preference for a single side chain conformer (chi(1) similar to 60 degrees). Low-energy conformers of this analog could only be effectively superimposed with low-energy conformers of the parent peptide in which the Phe(3) side chain conformation was limited to chi(1) similar to -60 degrees. This observation eliminates the last remaining uncertainty regarding conformational features of the pharmacophore elements in the delta receptor-bound;state, allowing the proposal of a complete model.
Link to Published Version
Mosberg, H. I., Omnaas, J. R., Lomize, A., Heyl, D. L., Nordan, I., Mousigian, C., … Porreca, F. (1994). Development of a model for the delta-opioid receptor pharmacophore .2. conformationally restricted phe(3) replacements in the cyclic delta-receptor selective tetrapeptide tyr-c[d-cys-phe-d-pen]oh (jom-13). Journal of Medicinal Chemistry, 37(25), 4384–4391. doi:10.1021/jm00051a016