Effective and safe analgesics represent an unmet medical
need for
the treatment of acute and chronic pain. A series of N-cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines
were designed, synthesized, and assayed, leading to the discovery
of a benzylamine derivative (compound 4, SLL-039) as
a highly selective and potent κ opioid agonist (κ, K
i = 0.47 nM, κ/μ = 682, κ/δ
= 283), which was confirmed by functional assays in vitro and antinociceptive assays in vivo. The in vivo effect could be blocked by pretreatment with the
selective κ antagonist nor-BNI. Moreover, this compound did
not induce sedation, a common dose limiting effect of κ opioid
receptor agonists, at its analgesic dose compared to U50,488H. The
dissociation of sedation/antinociception found in SLL-039 was assumed
to be correlated with the occupation of its benzamide motif in a unique
subsite involving V1182.63, W124EL1, and E209EL2.
The search for selective kappa opioid receptor (κOR) agonists with an improved safety profile is an area of interest in opioid research. In this work, a series of m-substituted analogs were designed, synthesized, and assayed, resulting in the identification of compound 6c (SLL-1206) as a κOR agonist with single-digit nanomolar activities. The subtype selectivity of compound 6c appeared to be a consequence of an enormous decrease in the affinity for μOR and δOR, rather than a significant increase in the affinity for κOR, which was not the case for SLL-039, another selective and potent κOR agonist identified in our previous work. Besides reduced central nervous system effects, SLL-1206 exhibited substantially improved physicochemical and pharmacokinetic properties compared with SLL-039, with increases of over 20-fold in aqueous solubility and approximately 40-fold in oral bioavailability in rats.
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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