Discovery of a Novel Class of Substituted Pyrrolooctahydroisoquinolines as Potent and Selective δ Opioid Agonists, Based on an Extension of the Message−Address Concept

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Abstract

This paper describes the design and synthesis of compounds belonging to a novel class of substituted pyrrolooctahydroisoquinolines which are potent and selective delta opioid agonists. Molecular modeling studies performed on known, selective delta ligands such as (+)-3 and the potent delta agonists SNC 80 led to the identification of the carboxamido moiety of the latter as a putative nonaromatic delta address. Insertion of this moiety onto the octahydroisoquinoline opioid message resulted in (+/-)-5b, a potent and selective delta ligand. The active enantiomer, (-)-5b, displayed nanomolar affinity for the delta receptor (Ki = 0.9 nM) with good mu/delta and kappa/delta binding selectivity ratios (140 and 1480, respectively). In addition, (-)-5b behaved as a full delta agonist in the mouse vas deferens bioassay having an IC50 = 25 nM and being antagonised in the presence of 30 nM naltrindole (NTI). These studies, based on the message-address concept, indicated that the nonaromatic (N,N-diethylamino)carbonyl moiety is a viable alternative to the classical benzene ring as a delta opioid address. Preliminary in vivo studies showed that (+/-)-5b produced a dose-related antinociception in the mouse abdominal constriction test after intracerebroventricular administration (ED50 = 1.6 micrograms/mouse).

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