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

Abstract

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.

Discovery of an Ortho-Substituted N-Cyclopropylmethyl-7α-phenyl-6,14-endoethano-tetrahydronorthebaine Derivative as a Selective and Potent Kappa Opioid Receptor Agonist with Subsided Sedative Effect

“…Contrary to this, SLL-627, considered a comparable chemotype, did not produce this adverse effect at analgesic doses. 38 In contrast, SLL-039, SLL-1206, and compound 7a showed minimal sedative effects. 34,36 The possible mechanism responsible for this is still a matter of speculation.…”

“…32,34,36,57 However, SLL-627 and compound 7a were also identified as full MOR agonists and exhibited a low sedative potential. 38 Since the antinociception produced by SLL-020ACP, SLL-627, and compound 7a was almost completely abolished upon pretreatment with the KOR-selective antagonist nor-BNI, the MOR component negligibly contributed to their in vivo profiles. Therefore, a correlation between the MOR functional activity and decreased sedation potential is unlikely.…”

“…However, this hypothesis was dismissed with subsequent discoveries of other morphinanbased selective KOR agonists, such as SLL-1206 and SLL-627, with low sedative potential without interacting with this subpocket. 36,38 Moreover, the variability in functional activity toward MOR might offer an alternative explanation. Despite the diversity in their subtype selectivity, nalfurafine and SLL-020ACP functioned as partial or full MOR agonists, whereas SLL-1206 and SLL-039 lacked intrinsic stimulatory activity to MOR.…”

“…The crystal structures of KOR (PDB entry, 6B73) and MOR (PDB entry, 5C1M) were retrieved from the Protein Data Bank (http://www.rcsb.org/). 41,42 Except the molecular structure of SLL-627 which was obtained from its crystal structure, 38 the three-…”

“…32,38 Despite their similar spatial assembly in structure, SLL-020ACP exhibited strong sedative effects in the locomotor activity test, 36 a response absent in SLL-627. 38 In contrast, the 7α-phenyl-6,14-endoethano-tetrahydronorthebaines SLL-039 and SLL-1206, acting as potent and selective KOR agonists in vitro and in vivo, showed neither aversive nor sedative effects at analgesic doses in rodent models. 34,36 As shown in our previous study, 34,36 the structure−activity relationship (SAR) profile for KOR activity was analyzed for 7αphenyl-6,14-endoethano-tetrahydro northebaines with para-or meta-substituents on the terminal benzene ring.…”