Drug design and synthesis of ε opioid receptor agonist: 17-(cyclopropylmethyl)-4,5α-epoxy-3,6β-dihydroxy-6,14-endoethenomorphinan-7α-( N-methyl- N-phenethyl)carboxamide (TAN-821) inducing antinociception mediated by putative ε opioid receptor

Abstract

Here we report the new drug design and synthesis of a series of 6,14-endoethenomorphinan-7-carboxamide derivatives as a putative ε opioid receptor agonist. One of these compounds, 17-(cyclopropylmethyl)-4,5α-epoxy-3,6β-dihydroxy-6,14-endoethenomorphinan-7α-( N-methyl- N-phenethyl)carboxamide (TAN-821), showed agonistic activity for a putative ε opioid receptor (IC 50 = 71.71 nM) in the rat vas deferens (RVD) preparations. TAN-821 stimulated the binding of the nonhydrolyzable guanosine 5 ′-triphosphate analog, guanosine 5 ′-(γ-thio)-triphosphate (GTPγS), to the mouse pons/medulla membrane via the activation of putative ε opioid receptor. Moreover, TAN-821 given intracerbroventricularly (i.c.v.) produced a marked antinociception in the tail-flick test (ED 50 = 1.73 μg) and the hot-plate test (ED 50 = 2.05 μg) in a dose-dependent manner. The antinociception induced by TAN-821 administered i.c.v. was blocked by the i.c.v.-pretreatment with a putative ε opioid receptor partial agonist β-endorphin [1–27], but not a μ opioid receptor antagonist β-FNA, a δ opioid receptor antagonist NTI, or a κ opioid receptor antagonist nor-BNI. The present results suggest that TAN-821 may be a useful tool for the investigation on the pharmacological properties of the putative ε opioid receptor.