Discovery of a Highly Selective and Potent κ Opioid Receptor Agonist from N-Cyclopropylmethyl-7α-phenyl-6,14-endoethanotetrahydronorthebaines with Reduced Central Nervous System (CNS) Side Effects Navigated by the Message–Address Concept

Abstract

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.

Exploration of the SAR Connection between Morphinan- and Arylacetamide-Based κ Opioid Receptor (κOR) Agonists Using the Strategy of Bridging

“…As shown in Figure b, despite the fact that a similar spatial orientation was found for the arylacetamidyl substituents between U50,488H and morphinan-based compounds 4b and 4j in the κOR pocket, poor local overlaps of the arylacetamidyl groups were observed. Besides, the molecular length of U50,488H was too short to reach the unique subpocket seated at the top of TM2 domain, which was proposed to be critical for the κOR subtype selectivity and potency of morphinan-based SLL-039 . Therefore, on the basis of the analysis of SARs for morphinan-based 7α-arylacetamides and superposition of modeled κOR complex, it seemed that our 7α-arylacetamidyl substituents failed to reproduce the pharmacological profile of classical arylacetamides and the docked patterns did not fit to each other in the κOR binding pocket despite the presence of same arylacetamidyl substituents.…”

“…A series of N -cyclopropylmethyl-7α-arylacetamidylphenyl-6,14-endoethano-tetrahydronorthebaine analogues were synthesized in a similar way as described in our previous work, , which was depicted in Scheme . With the aniline 3 as the key intermediate, the final products 4b – q were prepared with a variety of acids under appropriate conditions.…”

“…This profile seemed to be a unique feature of compound 4j and could not be reproduced by compound 4b with a 3′,4′-dicholorphenylacetamidyl substituent or compounds 4k – l with a 3′- or 4′-methylphenylacetamidyl substituent. Specially, compound 5 , which was obtained by introducing a methyl on the amide of compound 4j , showed almost no subtype selectivity (κ/μ = 0.3, κ/δ = 2.5); Moreover, compound 4j displayed a similar binding profile and subtype selectivity comparable to SLL-039 with a benzamidyl substituent, which was subsequently identified as a potent and highly selective κOR agonist both in vitro and in vivo …”

“…The synthesis of northebaine hydrochloride and compounds 1 – 3 was according to the procedure described in our previous work. , …”

“…As part of our ongoing efforts − to develop κOR modulators from morphinan-based scaffold, SLL-039 (Figure ), an N -cyclopropylmethyl-7α-phenyl-6,14-endoethano­tetrahydronorthebaine analogue, was identified as a highly selective and potent κOR agonist . Additionally, SLL-039 did not produce significant sedative effects compared with U50,488H at relevant doses for analgesia in rodent models.…”