Design, Synthesis, and Biological Evaluation of the Third Generation 17-Cyclopropylmethyl-3,14ß-dihydroxy-4,5α-epoxy-6ß-[(4'-pyridyl)carboxamido]morphinan (NAP) Derivatives as µ/κ Opioid Receptor Dual Selective Ligands.
J Med Chem
; 62(2): 561-574, 2019 01 24.
Article
en En
| MEDLINE
| ID: mdl-30608693
ABSTRACT
µ opioid receptor (MOR) agonists have been widely applied for treating moderate to severe pain. However, numerous adverse effects have been associated with their application, including opioid-induced constipation (OIC), respiratory depression, and addiction. On the basis of previous work in our laboratory, NAP, a 6ß- N-4'-pyridyl substituted naltrexamine derivative, was identified as a peripheral MOR antagonist that may be used to treat OIC. To further explore its structure-activity relationship, a new series of NAP derivatives were designed, synthesized, and biologically evaluated. Among these derivatives, NFP and NYP significantly antagonized the antinociception effect of morphine. Whereas NAP acted mainly peripherally, its derivatives NFP and NYP actually can act centrally. Furthermore, NFP produced significantly lesser withdrawal symptoms than naloxone at similar doses. These results suggest that NFP has the potential to be a lead compound to treat opioid abuse and addiction.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Diseño de Fármacos
/
Receptores Opioides kappa
/
Receptores Opioides mu
/
Morfinanos
Límite:
Animals
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2019
Tipo del documento:
Article
País de afiliación:
Estados Unidos