Original endomorphin-1 analogues exhibit good analgesic effects with minimal implications for human sperm motility

Abstract

To search a novel analgesic characterizes the effects on human sperm motility as minimal as possible. A new class of endomorphin-1 (EM-1) analogues was synthesized by combining successful chemical modifications including N-terminal guanidino modification, Phe4 was chlorinated, replaced of l-Pro2-Trp3 by d-Ala2-Gly3 or d-Pro2-Gly3 at position 2 and 3. Their bioactivities were measured by radioligand binding assay, metabolic stability, antinociception activity and sperm motility effects. In radioligand binding assays, analogue GAGP shown a μ-opioid receptor affinity about 17.7-fold higher and a 57.3-fold higher δ-opioid receptor affinity than EM-1. In the metabolic stability assays, GAGP had the longest half-lives and 16.6-fold higher than EM-1. In the tail-flick test in mice, GAGP showed the best analgesia. In sperm motility assays, the group of GAGP (10−5, 10−7mol/L) decreased of the percentage of a+b grade, and no significant when compared with initial value. In GAGP (10−6mol/L) group, sperm motility was progressively increased, although it was not statistically significant. But at the groups of morphine (10−7mol/L) and GAGD (10−7mol/L), these caused significant reduction between 0 and 90 min. We found that analogues GAGP, activating μ-opioid receptor and partial δ-opioid receptor, exhibit good analgesic effects with minimal implications for human sperm motility. It might be important in potential application as drug candidates of analgesic without implications for human sperm motility.