Opiate receptor binding, guinea pig ileum activity, and prolonged analgesia induced by the brain peptide Tyr-W-MIF-1 and two potent analogs

Abstract

Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH 2) is a peptide isolated from human and bovine brain with opiate activity. Two synthetic analogs of Tyr-W-MIF-1 were compared with the parent compound, DAMGO and Tyr-MIF-1 for (a) binding to opiate receptors (b) activity in the guinea pig ileum assay, and (c) analgesic activity after ICV administration to the rat. All compounds tested showed preferential binding to mu receptors. Tyr-MIF-1 showed relatively low affinity, but high selectivity (∼400-fold selectivity for mu over delta and more than 500-fold selective for mu over kappa sites). Tyr-W-MIF-1, which induces prolonged analgesia after ICV administration, showed affinity for mu sites that was 10-fold higher than Tyr-MIF-1 while retaining 200-fold selectivity for mu over delta and kappa sites. Two cyclized analogs of Tyr-W-MIF-1 approached the potency of DAMGO in several assays. The analogs showed 50- and 20-fold increases in affinity (IC 50 of 6 and 18 nM) for the mu site relative to Tyr-W-MIF-1, with 50-fold selectivity for mu over delta sites, and lack of binding to non-opiate Tyr-MIF-1 sites. The analogs were active in the guinea pig ileum assay with IC 50s of 10 and 30 nM. Dose-dependent analgesia after ICV administration of one of the analogs persisted for about an hr after 1 μg, for 3 hr after 25 μg, and for more than 6 hr after 100 μg. For both analogs, analgesia after 1 μg was similar to that seen with DAMGO. Thus, an endogenous brain peptide (Tyr-W-MIF-1) that does not contain the sequence Tyr-Gly-Gly, together with its structural analogs, can provide a range of selectivity patterns for binding to opiate receptors and potent opiate agonist activity.