Methadone conformation

Representation of a probable conformation of methadone hydrochloride (N Me groups are omitted). 

The ethyl ester analogue of methadone is a further stereochemical anomaly in the methadone group. The S-(+) ester (LXXl) is weaker than ( )-antipode [267]. Conformational differences between methadone and the ester (LXXI)... 

The potent analgesic methadone (143) may adopt a conformation like that of pethidine if the dimethylamino and carbonyl groups interact, and so it may be regarded as an analogue... 

Probable conformations for methadone (31) and the N-benzylmethyl-aminoanilide 32, based upon spectroscopic and X-ray crystallographic studies, have been proposed.<92,93) If it is assumed that these conformations are likely to resemble those adopted by the analgesic at the receptor site, and further that the phenyl-sec-methyl-basic center orientation of the methadone... 

In the case of methadone and its congeners, the dual diphenyl system (CPh2) does not lead to specially elevated potencies, and it is possible that one phenyl ring serves as a steric restraint for the other in achievement of an active conformation. High orders of activity are found in oripavine derivatives without inclusion of extra aromatic elements, but all potent derivatives have extensive additional hydrocarbon elements attached to the morphine skeleton. 

Many conformational options are open to acyclic analgesics like methadone and the thiambutenes, and it is not unlikely that some may have an aromatic and basic group suitably aligned for association at the morphine-... 

The relatively low potencies of analgesics such as methadone and dex-tromoramide, also with dual aromatic features, are considered due to the fact that they cannot assume the critical conformation of rings A and F proposed for the potent derivatives. Conversely, however, it is difficult to account for the low orders of potencies (on the scale of the compounds of Fig. 13.9) of the 4-phenylpiperidines 35 that are capable of conversion to conformations appropriate to high activity (provided energy barriers may be overcome and/or compensated for) the derivative 36 presents little difficulty in this respect. There are clearly hazards in attempting the correlation of aromatic molecular features in ligands of disparate structure. 

Fig. 8.2 Two-dimensional structures of l-methadone and the enol tautomer of l-methadone together with three-dimensional space-filling baU-and-stick (la, c and 2a, c) and CPK models (lb, d and 2b, d) for l-methadone and its enol tautomer, respectively. The models of l-methadone show one of many possible conformations while the models of the enol form show the molecule locked by the intramolecular...

Morphine is a very rigid molecule, because it has very few bonds that undergo free rotation. As a result, the pharmacophore is locked in place. In contrast, flexible molecules are capable of adopting a variety of conformations, and only some of those conformations can bind to the receptor. For example, methadone has many single bonds, each of which undergoes free rotation ... 

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