New benzomorphan derivatives of MPCB as MOP and KOP receptor ligands.
There is considerable interest in developing KOP Opioid receptor ligands as clinically useful analgesics. Moreover, compounds with mixed KOP receptor and mu-opioid peptide (MOP) receptor agonist/antagonist properties could have a better therapeutic potential. The benzomorphan-based synthetic ligands MPCB and CCB have been shown to bind KOP receptors with high affinity and selectivity. We report here a series of compounds synthesized to perform structure-affinity relationship (SAR) studies on MPCB. The aim of this study was to optimise KOP receptor-ligand interaction and to modulate MOP receptor selectivity. In the benzylamide analogue of MPCB (compound 9) the presence of a third aromatic nucleus, at an appropriate distance and conformation with respect to aromatic pharmacophoric residues, increased KOP receptor affinity by about 6-fold compared to MPCB (Ki = 35 nM and Ki = 240 nM, respectively). Instead, compound 28 with a tertiary amino group in the nitrogen substituent displayed a comparable KOP receptor affinity (Ki = 179 nM) but also high MOP receptor affinity (Ki = 45 nM). Thus, the present study shows that in benzomorphan-based ligands the presence of different functional groups in the nitrogen substituent, ranging from a positive charged amine to an additional aromatic ring, is able to promote the correct aligment of aromatic pharmacophoric residues with MOP and KOP receptor types. Evaluation of docking simulations of compounds 9 and 28 into the KOP and MOP receptor displayed selective ligand interactions with the important amino acid residues Tyr320 (TMVII) and Trp318 (TMVII), respectively.
Department of Pharmaceutical Sciences, University of Catania, Italy. lpasquin@unict.it
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D000818:Animals; D001575:Benzomorphans / Q000737:chemistry* / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003496:Cyclazocine / Q000031:analogs & derivatives* / Q000737:chemistry; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000187:drug effects; D017473:Receptors, Opioid, kappa / Q000187:drug effects*; D017450:Receptors, Opioid, mu / Q000187:drug effects*; D013329:Structure-Activity Relationship
C110285:6,11-dimethyl-1,2,3,4,5,6-hexahydro-3-((2'-(methoxycarbonyl)-2'-phenylcyclopropyl)methyl)-2,6-methano-3-benzazocin-8-ol; D001575:Benzomorphans; D007202:Indicators and Reagents; D008024:Ligands; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D003496:Cyclazocine