Conformational preferences of the kappa-selective opioid agonist U50488. A combined molecular mechanics and nuclear magnetic resonance study.
The conformational preferences of the kappa-selective opioid agonist U50488 have been studied using MM2-87 calculations and nuclear magnetic resonance (NMR) spectroscopy. The calculations were performed for the protonated form with a dielectric constant of 80 and the unprotonated form with dielectric constants of 1.5 and 80. A systematic search found 72 stable conformers with certain consistent conformational preferences for some of the important dihedral angles. The preferred conformers proved to be compact structures stabilized by intramolecular attractive van der Waals interactions, though at least some of these appear to be electrostatically unfavorable. The conformation of U50488 was also examined in aqueous solution using one-dimensional (1D) and two-dimensional (2D) high-resolution 1H NMR techniques such as the interpretation of 1H-1H vicinal coupling constants, 1D and 2D nuclear Overhauser effect (NOE) experiments, and 2D correlated spectroscopy (COSY) experiments. Five crystallographic conformations were examined as well. There was generally good agreement between all three methods of conformational analysis. There appeared to be a reasonable geometrical agreement between the relatively rigid kappa-agonist (-)-ketazocine and a gauche conformer of U50488. The proposed pharmacophore is also consistent with other kappa-selective analogs of U50488 including one in which the peptide bond is incorporated into a lactam ring. The low affinity of U50488 for mu-receptors was attributed to its cyclohexane ring which occupies space not present in the nonselective (-)-ketazocine.
Froimowitz
M
M
Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02178.
DiMeglio
C M
CM
Makriyannis
A
A
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000700:Analgesics / Q000737:chemistry*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D011759:Pyrrolidines / Q000737:chemistry*; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D013816:Thermodynamics
D000700:Analgesics; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer