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

This paper describes the design and synthesis of compounds belonging to a novel class of substituted pyrrolooctahydroisoquinolines which are potent and selective δ opioid agonists. Molecular modeling studies performed on known, selective δ ligands such as (+)-3 and the potent δ agonist SNC 80 led to the identification of the carboxamido moiety of the latter as a putative nonaromatic δ address. Insertion of this moiety onto the octahydroisoquinoline opioid message resulted in (±)-5b, a potent and selective δ ligand. The active enantiomer, (−)-5b, displayed nanomolar affinity for the δ receptor (Ki = 0.9 nM) with good μ/δ and κ/δ binding selectivity ratios (140 and 1480, respectively). In addition, (−)-5b behaved as a full δ 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 classi...