Development of a model for the delta-opioid receptor pharmacophore. 4. Residue 3 dehydrophenylalanine analogues of Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13) confirm required gauche orientation of aromatic side chain.

Abstract:

:We have previously proposed a model for the delta-opioid receptor binding conformation of the high affinity tetrapeptide Tyr-c[D-Cys-Phe-D-Pen]OH (JOM-13) based on experimental and theoretical conformational analysis of this peptide and a correlation of conformational preferences of further conformationally restricted analogues of this tetrapeptide with their receptor binding affinities. A key element of this model is the requirement that the Phe3 side chain exist in the chi 1 = -60 degrees conformation. Conformational calculations on the residue 3 dehydrophenylalanine analogues of JOM-13 suggest that while the dehydro (Z) phenylalanine analogue can be superimposed easily with the proposed binding conformer of JOM-13, the dehydro(E)phenylalanine analogue cannot. These results lead to the prediction that the dehydro(Z)phenylalanine analogue should display similar delta-receptor binding affinity as JOM-13 while the dehydro(E)phenylalanine analogue is expected to bind less avidly. Synthesis and subsequent opioid receptor binding analysis of the dehydrophenylalanine analogues of JOM-13 confirm these predictions, lending support to the delta-pharmacophore model.

journal_name

Biopolymers

journal_title

Biopolymers

authors

Mosberg HI,Dua RK,Pogozheva ID,Lomize AL

doi

10.1002/(sici)1097-0282(199609)39:3<287::aid-bip2>

subject

Has Abstract

pub_date

1996-09-01 00:00:00

pages

287-96

issue

3

eissn

0006-3525

issn

1097-0282

pii

10.1002/(SICI)1097-0282(199609)39:3<287::AID-BIP2>

journal_volume

39

pub_type

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