Basic Nitrogen and C-14 Substituents

More detailed consideration will now be given to the influence of N- and C-14 (=C-11 in benzomorphans) substituent structure upon the pharmacological profile of opoid ligands. 

Agonist activity was considerably reduced in the isomorphan analogs of Nos 2 (NMe) and 8 (NCBM), most dextro isomers had very low potencies in either test Versus oxymorhponc in mouse Straub tail test (OMST) d Mouse writhing lest 

Agonist and antagonist ligands are influenced in the same way by the presence of a phenolic hydropxyl at C-3, as is evident from relative potencies of many free phenol- O-methylated pairs of antagonists (e.g., 32).(32) However, like 3-deoxymorphines and morphinans (p. 119), absence of this feature in antagonists may be compensated by a 4-methoxy substituent. Thus the 4-methoxy derivatives 33 all have had narcotic antagonist action with at least pentazocine-level antinociceptive effects in mice.(86) 

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  

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