Rational Drug Design of Selective ɛOpioid Receptor Agonist TAN-821 and Antagonist TAN-1014

β-Endorphin (β-EP) is generally classified as aμ;andδ;opioid receptor agonist but is also an agonist of theɛopioid receptor. Although several selective agonists and antagonists for m, d, and k opioid receptors are known, selectiveɛreceptor agonists or antagonists have not been reported for some time. Recently, we designed and synthesized the selectiveɛreceptor agonist, 17-(cyclopropylmethyl)-4,5α-epoxy-3,6β- dihydroxy-6,14-endoethenomorphinan-7α-[N-methyl-N-phenethyl]carboxamide (TAN-821), and the selective e receptor antagonist, 17-(cyclopropylmethyl)-4,5α-epoxy-6b,21-epoxymethano-3-hydroxy-6,14-endoethenomorphinan- 7α-(N-phenethyl)carboxamide (TAN-1014). TAN-821 stimulated binding of the nonhydrolyzable guanosine 5'-triphosphate analogue, guanosine 5'-(γ-thio)-triphosphate (GTPgS), to the mouse pons/medulla membrane via activation of theɛreceptor. Moreover, TAN-821 given intracerebroventricularly (i.c.v.) produced marked, lonγ;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 e opioid receptor partial agonist β-EP (1-27), but not theμ;opioid receptor antagonist β-FNA, theδ;opioid receptor antagonist NTI, or the k 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 β-EP. These results suggest that TAN-821 and TAN-1014 are respectively a selectiveɛreceptor agonist and antagonist and that they may be useful tools for investigating the pharmacological properties of theɛopioid receptor.