Structure-activity studies of narcotic agonists and antagonists from quantum chemical calculations
Abstract
Three classes of flexible opiates have been studied: 4-phenyl piperdines, methadone and enkephalins. Our results show that low energy conformers of the 4-phenyl piperidines have equatorial phenyl rings and cannot completely overlap with rigid opiates at the receptor. A combination of calculated conformational and electronic properties could account for observed potency differences in meperidine, desmethyl, alpha+, alpha-, beta+ and beta- prodines. Our results also indicate that both meperidine and its reverse ester bind to the receptor in a similar mode with the phi ring in approximmately the same position as the phenyl substituent in 5-phenyl benzomorphans. Conformers of methadone which maximally resemble morphine have very high relative energies. The lowest energy conformer has a partial H-bond between the NH and O=C groups. In this conformation methadone resembles meperidine more than morphine. The electronic structure of all three types of opiates indicate a similar cationic charge distribution around the amine nitrogen and imply that their binding to an anionic receptor site could be similar. The determination of peptide opiate conformations present a challenge of a different order of magnitude than the most flexibe exogenous opiates. Because of the extremely large number of possible conformations, search strategies based on energy optimized conformations alone are not adequate to select plausible receptor site candidates. Other criteria such as consistency with known…
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