Synthesis, opioid receptor binding, and biological activities of naltrexone-derived pyrido- and pyrimidomorphinans

A series of pyrido- and pyrimidomorphinans (6a-h and 7a-g) were synthesized from naltrexone and evaluated for binding and biological activity at the o pioid receptors. The unsubstituted pyridine 6a displayed high affinities at opioid delta, mu, and kappa receptors with Ki values of 0.78, 1.5, and 8.8 nM, respectively. Compound 6a was devoid of agonist activity in the mouse vas deferens (MVD) and guinea pig ileum (GPI) preparations but was found to display moderate to weak antagonist activity in the MVD and CPI with K-e v alues of 37 and 164 nM, respectively. The pyrimidomorphinans in general dis played lower binding potencies and 6 receptor binding selectivities than th eir pyridine counterparts. Incorporation of aryl groups as putative 6 addre ss mimics on the pyrido- and pyrimidomorphinan framework gave ligands with significant differences in binding affinity and intrinsic activity. Attachm ent of a phenyl group at the 4'-position of 6a or the equivalent 6'-positio n of 7a led to dramatic reduction in binding potencies at all the three opi oid receptors, indicating the existence of a somewhat similar steric constr aint at the ligand binding sites of delta, mu, and kappa receptors. In cont rast, the introduction of a phenyl group at the 6'-position of 6a did not c ause any reduction in the binding affinity at the 6 receptor. In comparison to the unsubstituted pyridine 6a, the 5'-phenylpyridine 6c showed improvem ents in mu/delta and kappa/delta binding selectivity ratios as well as in t he 6 antagonist potency in the MVD. Interestingly, introduction of a chlori ne atom at the para position of the pendant 5'-phenyl group of 6c not only provided further improvements in 6 antagonist potency in the MVD but also s hifted the intrinsic activity profile of sc from an antagonist to that of a mu agonist in the GPI. Compound Sd thus possesses the characteristics of a nonpeptide mu agonist/delta antagonist ligand with high affinity at the 6 receptor (Ki = 2.2 nM), high antagonist potency in the MVD (K-e, = 0.66 nM) , and moderate agonist potency in the GPI (IC50 = 163 nM). Antinociceptive evaluations in mice showed that intracerebroventricular (icv) injections of 6d produced a partial agonist effect in the 55 degrees C tail-flick assay and a full agonist effect in the acetic acid writhing assay (A(50) = 7.5 nm ol). No signs of overt toxicity were observed with this compound in the dos e ranges tested. Moreover, repeated icy injections of an A(90) dose did not induce any significant development of antinociceptive tolerance in the ace tic acid writhing assay. The potent 6 antagonist component of this mixed mu agonist/delta antagonist may be responsible for the diminished propensity to produce tolerance that this compound displays.