Conformational analogies of morphine agonists and antagonists as revealed by carbon‐13 NMR spectroscopy

Abstract

The extreme similarity (except in the vicinity of the nitrogen atom) of the 13C spectra of the agonist-antagonist pairs oxymorphone-naloxone and morphine-nalorphine and their respective hydrochlorides suggests that the N-methyl and N-aUyl compounds have analogous conformations. This makes unlikely an interpretation of the agonist-antagonist dichotomy in terms of confonnational differences. Both morphine hydrochloride and nalorphine hydrochloride exist as mixtures of two diastereomers: ca 83% of the isomer with equatorial N-akyl and 17% of the isomer with axial N-aikyl (AG'=O.95 kcalmol-I).

Complete proton and carbon nuclear magnetic resonance spectral assignments of some morphinan‐6‐one alkaloids by two‐dimensional NMR techniques

“…The N-C-16 bond is longer in 5 by 0.041 (5) A, N-CH, is longer by 0.028 (5) A and N-C-19 is longer by 0.066 (4) A. There were no significant differences in the other bond lengths.…”

“…3). When the H-lOqe proton in 2, 4 or 5 was irradiated a strong NOE was observed for the H-lOqa, H-1 and NCH, protons (Fig. 4).…”

“…oxycodone (2), naloxone (R' = H, R = CH,CH=CH,) and naltrexone (R' = H, R = CH,-c-C,H,)] are important because of their role in controling varied pharmacological behaviors.' However, complete proton ('H) and carbon (',C) nuclear magnetic resonance (NMR) peak assignments for 1 and 2 and some important quaternary * Author to whom correspondence should be addressed nitrogen-substituted alkaloids (3)(4)(5)(6) are fragmentary or, to our knowledge, not present in the literature. We have coilected 'H (400 MHz) and I3C (100 MHz) NMR chemical shift and proton coupling constant data for 1-6 and assigned the spectra using a variety of twodimensional NMR techniques.…”

“…Severa1 workers have performed NMR conformational analyses of 1-3. Perly et al ' have obtained 'H chemical shift and proton coupling constant data for 3, Glasel and Reiher3 proton coupling constant data for 1 and 3, Eliel et al 4 I3C chemical shift data for 1 and 3, Carro11 et I3C chemical shift data for 2 and Kelley et I3C chemical shift data for 3. Recently, we reported that the minor component observed in the aqueous 'H and 13C NMR spectra of 3 and 4 was produced by the reaction of these salts with water.…”

Stereochemistry of long-lasting opiates. 2. .delta.-Selective opiate antagonists and their agonist analogs

“…Axialequatorial equilibrium of the substituent on nitrogen was determined via a 13C NMR method. 18,19 The existence of the chair and boat forms of the C ring was established via 13C NMR and X-ray methods (the ring C contains the keto group of e.g. naloxone, ll).20,21 Also, the energy of the rotamers around the N-C and C-C bonds of the N-allyl and cyclopropylmethyl was calculated.22,23 Fine details of the stereochemistry of steroids in relation to their receptor binding and biological activity have already been reported by Duax et al24 On the other hand, very little is known about the stereochemistry of the azine bond.…”