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Current Medicinal Chemistry
ISSN (Print): 0929-8673
ISSN (Online): 1875-533X
VOLUME: 13
ISSUE: 10
DOI: 10.2174/092986706776360851      Price:  $58









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

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Author(s): H. Fujii and H. Nagase
Pages 1109-1118 (10)
Abstract:
β-Endorphin (β-EP) is generally classified as aμ;andδ;opioid receptor agonist but is also an agonist of theℇ opioid receptor. Although several selective agonists and antagonists for m, d, and k opioid receptors are known, selectiveℇ receptor agonists or antagonists have not been reported for some time. Recently, we designed and synthesized the selectiveℇ receptor 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 theℇ receptor. 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 selectiveℇ receptor agonist and antagonist and that they may be useful tools for investigating the pharmacological properties of theℇ opioid receptor.
Keywords:
e opioid receptor, β-endorphin, TAN-821, TAN-1014, analgesics, message-address concept, accessory site theory
Affiliation:
Pharmaceutical ResearchLaboratories, Toray Industries, Inc., 1111, Tebiro, Kamakura, Kanagawa,248-8555, Japan.