Aromatic Features

1500 x pethidine in mice (Potent analgesics with dual aromatic features) 

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. 

There is ample evidence of the importance of the relative placement and orientation of aromatic features to the rest of the molecule (notably the. basic area) in active derivatives, and binding interactions involving the basic and aromatic features of the ligand must be of primary importance in opioid receptor-ligand interactions. One example of the influence of phenyl orientation relative to the rest of the molecule is Portoghese s explanation of structure-activity variations among antipodal prodines and related compounds, as discussed in Chapter 7. 

Recent work indicates that the phenolic 3-OH of morphine does not play as vital a role as previously thought. Morphinan analogs that lack it have unchanged or elevated potencies provided a 4-phenolic (or better, 4-methoxy) substituent be present to compensate for the absence of the 4,5-oxide bridge of the natural alkaloids (p. 125). 

A range of oxygen functions is also met in the 3,3-diphenylpropylamine class of analgesic (R in 30) methadone (COEt, S02Et in sulfone analog), 

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The parent [6]radialene has no stabilizing aromatic feature and is predicted to have a relatively low-lying HOMO as compared to the lower members of the series, 1-399. This may explain why it is so highly reactive that it is difficult to handle. As far as the chemical behavior of the [6]radialenes is concerned, it is the hexamethyl derivative 150... 

Figure 16.3 P-gp-verapamil binding inhibition pharmacophore (orange, ring aromatic feature green, hydrogen bond acceptor cyan, hydrophobic features). Reprinted with permission from ref. [45], Copyright 2002 American Society for Pharmacology and Experimental Therapeutics.

Aihara introduced the term, three dimensional aromaticity (featured in the tide of his paper), to discuss doso-borane dianions in 1978 [12]. Jemmis and Schleyer applied the term to nido systems with six interstitial electrons [55], but their treatment emphasized the Hiickel analogy, rather than the spherical character. 

In the case of absence of the saturated carbon atoms, the bending and 1,2-allylic strains cannot be considered as the reasons for a flat potential energy surface around minimum. Therefore, it was suggested [27, 28] that the deviation of characteristics of cyclic conjugated systems from their aromatic features is responsible for conformational flexibility of such dihydroaromatic rings. In addition, it was demonstrated... 

Many conformational options are open to such 3-arylpiperidines, and it is reasonable to believe that some may provide a similar spatial relationship between the charged nitrogen and aromatic features as obtains in the rigid system of morphine (see 60). Parahydroxyphenyl analogs of the N-allyl and N-CPM derivatives were much less potent antagonists/79 results that emphasize the importance of a m-hydroxyphenyl moiety for ligands that bind to opioid receptors. 

To test the proposition that one of the phenyl rings of fentanyl was equivalent to the aromatic feature of morphine, Lobbezzo et al 33) prepared analogs of fentanyl with a phenolic OH group in either the 7V-phenethyl side... 

The spirane ring is formed by treating amides derived from 16 with formamide and reducing the product.(20,56) In the solid state the 4-NPh moiety adopts an equatorial rather than an axial conformation in relation to the piperidine ring,(57) akin to the solid and probable solute state conformation of fentanyl, for which there is X-ray<58) and H-nmr evidence (see 20). The activities of the spiranes 19 also provide evidence that anilido phenyl is a- rather than /3-oriented in active conformations of fentanyl derivatives (21). This aromatic feature is confined to the /3-orientation in the bicyclo analogs 22, neither of... 

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. 

Modeling of aromatic features depends on the selected pharmacophore scheme... 

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