Mu, delta, and kappa opiate receptor binding of Tyr-MIF-1 and of Tyr-W-MIF-1, its active fragments, and two potent analogs.
The relative binding to mu, delta, and kappa opiate receptors was characterized for the brain peptides Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2), Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH2), and two fragments of Tyr-W-MIF-1 (Tyr-Pro-Trp and Tyr-Pro-Trp-Gly) previously shown to have antagonist as well as agonist activity in the guinea pig ileum. Tyr-MIF-1 had relatively low affinity (Ki = 1 microM at the mu site) but high selectivity (400- and 700-fold greater affinity for mu over delta and mu over kappa binding). Tyr-W-MIF-1 (Ki = 71 nM at the mu site) showed higher affinity binding to all three sites than Tyr-MIF-1 while retaining 200-fold selectivity for mu over delta and kappa receptors. The affinity of the fragments of Tyr-W-MIF-1 was lower for mu but higher for delta receptors. We also tested two cyclized analogs of Tyr-W-MIF-1 that were about 200-fold more active than the parent compound in producing analgesia. These analogs showed higher affinity binding to all three opiate receptors. One of the analogs showed binding affinity to mu sites (Ki = 1.3 nM) that was within 3-fold of that of the potent analog of enkephalin, DAMGO. Thus, brain peptides with an N-terminal Tyr-Pro, rather than the Tyr-Gly-Gly-Phe sequence typical of other endogenous opiates, can provide high selectivity for mu opiate receptors. Analogs based on one of them, Tyr-Pro-Trp-Gly-NH2, show high affinity as well as potent analgesic activity.
Zadina
J E
JE
VA Medical Center, New Orleans, LA.
Kastin
A J
AJ
Ge
L J
LJ
Hackler
L
L
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain; D002531:Cerebellum; D004723:Endorphins / Q000378:metabolism; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000378:metabolism; D006168:Guinea Pigs; D009075:MSH Release-Inhibiting Hormone / Q000031:analogs & derivatives* / Q000378:metabolism; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000378:metabolism*; D051381:Rats; D011957:Receptors, Opioid / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013329:Structure-Activity Relationship; D013570:Synaptic Membranes / Q000378:metabolism
D004723:Endorphins; D004745:Enkephalins; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; C090788:tyrosyl-cyclo(lysyl-tryptophyl-glycyl); C090787:tyrosyl-cyclo(ornithyl-tryptophyl-glycyl); D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C077532:tyrosyl-prolyl-tryptophyl-glycinamide; C036930:tyrosyl-prolyl-leucyl-glycinamide; C044708:morphiceptin, N-Me-Phe(3)-; D009075:MSH Release-Inhibiting Hormone