THE ROLE OF THE “SPACER" IN THE OCTAHYDROISOQUINOLINE SERIES: DISCOVERY OF SB 213698, A NON-PEPTIDIC, POTENT AND SELECTIVE DELTA OPIOID AGONIST

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Abstract
Fragmentation of oxymorphindole led to a series of octahydroisoquinoline selective DELTA ligands. A SAR was performed in order to discover key medicinal chemistry features for optimisation of the DELTA agonist profile of this class of derivatives. Insertion of a sixmembered ring as “spacer" yielded to SB 213698 a potent and selective DELTA opioid agonist. SB 213698 reduced electrically-induced contractions in the mouse vas deferens (IC50 = 62 nM; antagonised by NTI); it was active in a dose-related manner in the mouse abdominal constriction test after i.c.v. and i.p. routes (ED50 = 2 μg/mouse and 0.13 mg/kg respectively). Antagonist studies proved that in vivo, SB 213698 acted through the activation of the DELTA receptor. This study demonstrated the crucial role played by the pyridine ring as “spacer" in orienting the DELTA address in the receptor agonist domain.