Identification of Opioid Ligands Possessing Mixed μ Agonist/δ Antagonist Activity among Pyridomorphinans Derived from Naloxone, Oxymorphone, and Hydropmorphone

Abstract

A series of pyridomorphinans derived from naloxone, oxymorphone, and hydromorphone (7a-k) were synthesized and evaluated for binding affinity at the opioid delta, micro, and kappa receptors in brain membranes using radioligand binding assays and for functional activity in vitro using [(35)S]GTP-gamma-S binding assays in brain tissues and bioassays using guinea pig ileum (GPI) and mouse vas deferens (MVD) smooth muscle preparations. The pyridine ring unsubstituted pyridomorphinans possessing the oxymorphone and hydromorphone framework displayed nearly equal binding affinity at the micro and delta receptors. Their affinities at the kappa site were nearly 10-fold less than their binding affinities at the micro and delta sites. Introduction of aryl substituents at the 5'-position on the pyridine ring improved the binding affinity at the delta site while decreasing the binding affinity at the micro site. Nearly all of the ligands possessing an N-methyl group at the17-position with or without a hydroxyl group at the 14-position of the morphinan moiety displayed agonist activity at the micro receptor with varying potencies and efficacies. In the [(35)S]GTP-gamma-S binding assays, most of these pyridomorphinans were devoid of any significant agonist activity at the delta and kappa receptors but displayed moderate to potent antagonist activity at the delta receptors. In antinociceptive evaluations using the warm-water tail-withdrawal assay in mice, the pyridomorphinans produced analgesic effects with varying potencies and efficacies when administered by the intracerebroventricular route. Among the ligands studied, the hydromorphone-derived 4-chlorophenylpyridomorphinan 7h was identified as a ligand possessing a promising profile of mixed micro agonist/delta antagonist activity in vitro and in vivo. In a repeated administration paradigm in which the standard micro agonist morphine produces significant tolerance, repeated administration of the micro agonist/delta antagonist ligand 7h produced no tolerance. These results indicate that appropriate molecular manipulations of the morphinan templates could provide ligands with mixed micro agonist/delta antagonist profiles and such ligands may have the potential of emerging as novel analgesic drugs devoid of tolerance, dependence, and related side effects.

Pyrrolo- and pyridomorphinans: Non-selective opioid antagonists and delta opioid agonists/mu opioid partial agonists

“…The pyridomorphinan 7a was reported as having no DOPr or KOPr agonist activity (though no antagonist activity could be detected) and extremely low potency MOPr partial agonist activity in a [ 35 S]GTPγS assay (EC 50 3000nM). 16 In isolated tissue assays the MOPr agonist activity of 7a was reported as being confirmed (IC 50 523 nM) in the guinea pig ileum (GPI: a tissue that is sensitive to agonists acting at MOPr and KOPr) but in mouse vas deferens (MVD: a tissue particularly sensitive to DOPr agonists, but also to MOPr and KOPr agonists) a DOPr partial agonist response was recorded (49% of maximum). 16 Thus the rank order of efficacies for opioid receptors of 7a appears to be MOPr>DOPr>KOPr with the major difference from 5b being the very low potency for all opioid receptor activity and particularly at DOPr where the efficacy difference was also very pronounced.…”

“…DOPr and KOPr affinity of 7a is also very much lower than that of 5b , 20-fold and 130-fold respectivly. 16 The effect of replacing the 17-methyl group of 5b with the CPM group ( 5k ) is relatively small since both ligands have high affinity for all three opioid receptors. Similar enhancement of binding affinity is seen in 7b in comparison with 7a ; in both series improvement in KOPr affinity is most pronounced.…”

[6,7]‐Heterocycle‐Fused 14‐Hydroxymorphinan Derivatives: Design, Synthesis, and Opioid Receptor Activity

“…Naltrindole (NTI, 1) [17,24] and b-FNA [25] were tested in our current assays as reference compounds. As expected, aminothiazole-derived 14-hydroxymorphinans 7 and 8 displayed binding preference for the m receptor, a profile different from NTI (1) and indoles 3-6 which were potent and selective for the d receptor.…”

“…1.97 (0.2 [17] , 1.6 [24] ) 151 AE14 [17] 75 AE 7 [17] 3 [24] 21.8 AE 7.0 1850 3160 4 [24] 4.50 AE 0. played good agonistic activity at the m receptor with efficacies (E max ) ranging from 82 to 117 % relative to DAMGO, indicating that they are all m agonists. To gain some insight on the different pharmacological profiles between the well-known d-selective antagonist naltrindole (1) and our current synthetic k agonists 8, 10, and 11, which also contain partial m agonism or antagonism, structural comparison of these compounds was conducted based on molecular superposition of the optimized structures of compounds 1, 8, and 10 ( Figure 1; conducted on energy-minimized conformations using the SYBYL molecular modeling software package).…”

Introduction to the Special Issue “Pharmacotherapies for the Treatment of Alcohol Abuse and Dependence” and a Summary of Patents Targeting other Neurotransmitter Systems

“…More selective opioid antagonists/modulators also have been developed and patented for treating alcoholism [256] such as those for the mu- [257, 258], delta- [259–265] and kappa- [266–268] opioid receptors. On the other hand, delta-mixed agonist/antagonist [260, 269–274] and agonists [275] have been patented to treat alcoholism as well. In addition, mixed opioid receptor modulators such as those for both the mu- and delta-receptor [262, 276, 277] also have been patented for treating alcoholism.…”