Rational drug design of selective ε opioid receptor agonist TAN-821 and antagonist TAN-1014

beta-Endorphin (beta-EP) is generally classified as a mu and delta opioid receptor agonist but is also an agonist of the E opioid receptor. Although several selective agonists and antagonists for mu, delta, and kappa opioid receptors are known, selective E receptor agonists or antagonists have not been reported for some time. Recently, we designed and synthesized the selective epsilon receptor agonist, 17-(cyclopropylmethyl)-4,5 alpha-epoxy-3,6 beta-dihydroxy-6,14-endoethenomorphinan-7 alpha-[N-methyl-N-phenethyl]carboxamide (TAN-821), and the selective epsilon receptor antagonist, 7 alpha-(cyclopropylmethyl)-4,5 alpha-epoxy-6 beta,21-epoxyniethano-3-hydroxy-6,14-endoethenomorphinan-7 alpha-(N-phenethyl)carboxamide (TAN-1014). TAN-821 stimulated binding of the nonhydrolyzable guanosine 5'-triphosphate analogue, guanosine 5'-(gamma-thio)-triphosphatc (GTP gamma S), to the mouse pons/medulla membrane via activation of the epsilon receptor. Moreover, TAN-821 given intracerebroventricularly (i.c.v.) produced marked, long-lasting, and dose-dependent antinociception in tail-flick and hot-plate tests. This antinociception induced by i.c.v. administered TAN-821 was blocked by i.c.v. pretreatment with the epsilon opioid receptor partial agonist beta-EP (1-27), but not the mu opioid receptor antagonist beta-FNA, the delta opioid receptor antagonist NTI, or the kappa opioid receptor antagonist nor-BNI. On the other hand, i.c.v. injection of TAN-1014 alone produced no antinociception, and i.c.v. pretreatment with TAN-1014 attenuated the antinociception induced by i.c.v beta-EP. These results suggest that TAN-821 and TAN-1014 are respectively a selective epsilon receptor agonist and antagonist and that they may be useful tools for investigating the pharmacological properties of the epsilon opioid receptor.