Undue central nervous system (CNS) side effects including
dysphoria
and sedation remain to be a challenge for the development of κ
opioid receptor (KOR) agonists as effective and safe analgesics. On
the basis of our previous work on morphinan-based KOR agonists, a
series of 7α-methyl-7β-substituted northebaine derivatives
were designed, synthesized, and biologically assayed. Among others,
compound 4a (SLL-627) has been identified
as a highly selective and potent KOR agonist both in vitro and in vivo, and its molecular basis was also examined
and discussed. Besides low liability to conditioned place aversion
(CPA) test, treatment of SLL-627 was associated with
a nonreduction in locomotor activity, compared to most of the other
arylacetamide- or morphinan-based KOR agonists which generally exhibited
apparently sedative effects. This unexpected finding provides new
insights to dissociate analgesia from sedation for future discovery
of innovative KOR agonists.
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