Naloxone, conformation

The stereodrawing of morphine plotted by a computer program (41) and based on the coordinates and thermal parameters experimentally determined by X-ray analysis of a crystal of the HBr salt (42) has been oriented to show the characteristic T shape of the molecule (or ion with the protonated N) in Fig. 20(a). Naloxone, a potent narcotic antagonist, differs from morphine chemically in the substitution of an allyl chain for the methyl group on the N atom, the substitution of OH for H at C-14, the saturation of the C-7-C-8 bond, and a carbonyl oxygen at C-6 rather than a hydroxyl. The stereodrawing of naloxone in Fig. 20(b) shows that morphine and naloxone (43) have identical molecular conformations, except for atoms C-6 and C-7 in ring D. 

Fig. 20. A comparison of the conformations of (a) morphine (42), (b) naloxone (43), (c) l-bromo-4-hydroxy-A -methylmorphinan-6-one (45), (d) a 3,4-methylenedioxy-substituted morphinanone (solid line) and a 4-methoxy-substituted morphinanone (dotted lines) (44), and (e) cyclazocine (46). In all molecules, the ellipsoids represent the experimentally determined thermal parameters at the 50% probability level. Hydrogen atoms have been omitted in (d).

The ring system in cyclazocine is abbreviated as compared with morphine or the morphinanones nonetheless, the remaining atoms can be superimposed very closely over those of morphine, naloxone, and the agonists shown in Fig. 20(a - d). In other words, crystal structure analyses have shown that all six substances have an almost common geometrical arrangement. In this class of substances, the differences in their activities have to be attributed largely to factors other than conformation. 

A hypothesis has been advanced to explain the different pharmacological response to opioid agonists and antagonists in terms of conformational differences about the basic center, as discussed in Chapter 13. However, a study by 13C-nmr of two such pairs (morphine-nalorphine, oxymorphone-naloxone) revealed little difference between agonist and antagonist molecules in either piperidine ring conformation (chairs only) or ratio of N- R axial to equatorial forms (83 17 for morphine, virtually 100% eq JV-R for 14-OH derivatives).035 ... 

Their results are summarized in Figure 5.9 similar conformations were proposed for the 14-hydroxy analogues naloxone and naltrexone [41]. 

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