Discovery of an M-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaine as a Selective, Potent, and Orally Active κ-Opioid Receptor Agonist with an Improved Central Nervous System Safety Profile

Abstract

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.

SLL-627 Is a Highly Selective and Potent κ Opioid Receptor (KOR) Agonist with an Unexpected Nonreduction in Locomotor Activity

“…As the positive control, U50,488H at an antinociceptive ED 50 dose of 5 mg/kg produced significant CPA. In contrast, SLL-039 and SLL-1206 , another two morphinan-based selective KOR agonists, also exhibited significant less aversion at effective analgesic doses compared to U50,488H , as shown in our previous work. , …”

“… a Potency and efficacy in stimulating [ 35 S]­GTPγS binding to membranes of CHO cells stably expressing opioid receptors. Data are expressed as the mean ± SEM of independent experiments performed in triplicate. b Not applicable. c Stimulation of [ 35 S]­GTPγS at 10 μM. d The data of U50,488H was consistent with the results from our previous reports. , …”

“…As shown in Figure , SLL-627 did not significantly inhibit locomotor activity at doses of 0.1 and 1.7 mg/kg. In contrast, we previously found that typical KOR agonists U50,488H and SLL-020ACP produced significant sedation at lower doses of analgesia in locomotor activity assay, but such apparent sedative effects were not observed for SLL-039 and SLL-1206 . , …”

“…However, the idea that KOR stimulation is associated with both analgesia and the undue central nervous system (CNS) effects was challenged by the discovery of nalfurafine (also known as TRK-820, Figure ), a potent, selective and centrally penetrant KOR agonist identified from 4,5-epoxymorphinan derivatives, which displayed a substantial reduction in dysphoria compared to other KOR agonists. , This finding was also confirmed in clinical studies and postmarketing surveillance. − Although treatment of nalfurafine was associated with a strong antinociceptive effect in vivo , it was repurposed to as an antipruritic at lower treatment doses due to unacceptable sedation at analgesic doses. , Additionally, another two 4,5-epoxymorphinan derivatives, SLL-039 and SLL-1206 (Figure ), have been identified to be potent and selective KOR agonists without producing significant sedation even at higher doses than those of analgesia compared to U50,488 in rodent models, as described in our previous work. , Therefore, nalfurafine is not an outlier and the chemotype of 4,5-epoxymorphinan might represent a valuable source to identify potential KOR agonists with more favorable CNS side-effects, which provides a basis for development of innovative pharmacological tools and drug candidates.…”

“…Third, the spatial assembly of C7β-adducts and their derivatives seems to be similar to that of nalfurafine, which is one of the selective KOR agonists available in clinical practice. The dose-limiting sedative effect of nalfurafine was also observed in SLL-020ACP but not in SLL-039 and SLL-1206 , with the accurate molecular mechanism unknown. , Therefore, it is also interesting to examine the sedation potential of C7β-adducts and their derivatives to search for any structural signature associated with reduced sedation and/or other CNS side-effects for 4,5-epoxymorphinan-based KOR agonists. Thus, as a part of our ongoing work on 4,5-epoxymorphinan derivatives, we here demonstrate that structural variation of the 4,5-epoxymorphinan scaffold could produce a novel selective and potent KOR agonist with an unexpected profile in locomotor activity through design, synthesis, and biological assays of a series of 7β-epimers of nepenthone derivatives with a 7α-methyl substituent. ,,,− …”