Importance of the stereo-orientation of aromatic groups in enkephalins to opiate receptor recognition.
PO +Dehydrophenylalanine (delta Phe) having the E-configuration (delta EPhe ; phenyl and C = O cis) was incorporated into [Leu5]-enkephalin in order to restrict its conformation. Compared with the Z-isomer, in the radio-ligand receptor binding assays, [D-Ala2, delta EPhe4 , Leu5] enkephalin showed drastically decreased potency for the delta and mu opiate receptors, i.e., 260- and 150-fold loss of affinity, respectively. The results strongly indicate that the opiate receptors require the Z-configuration (phenyl and C = O, trans) of the delta Phe4 residue and may require a specific interrelationship between the aromatic rings of the Tyr1 and Phe4 residues in the molecule for binding. The conformation of [Leu5]-enkephalin specific for the delta receptors was analyzed and a comparison made with its crystal structure recently elucidated.
D000818:Animals; D001921:Brain / Q000378:metabolism; D004745:Enkephalins / Q000378:metabolism*; D008968:Molecular Conformation; D011869:Radioligand Assay; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004745:Enkephalins; D011957:Receptors, Opioid