ABSTRACT
A series of 6-bicycloaryloxynicotinamides were identified as opioid receptor antagonists at mu, kappa, and delta receptors. Compounds in the 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide scaffold exhibited potent in vitro functional antagonism at all three receptors.
Subject(s)
Amides/chemistry , Carboxylic Acids/chemistry , Ethers/chemistry , Ethers/pharmacology , Narcotic Antagonists , Acrylic Resins/chemistry , Ethers/chemical synthesis , Molecular Structure , Receptors, Opioid/metabolism , Structure-Activity RelationshipABSTRACT
A structurally unique and new class of opioid receptor antagonists (OpRAs) that bear no structural resemblance with morphine or endogenous opioid peptides has been discovered. A series of carboxamido-biaryl ethers were identified as potent receptor antagonists against mu, kappa and delta opioid receptors. The structure-activity relationship indicated para-substituted aryloxyaryl primary carboxamide bearing an amine tether on the distal phenyl ring was optimal for potent in vitro functional antagonism against three opioid receptor subtypes.
Subject(s)
Ethers/chemical synthesis , Ethers/pharmacology , Narcotic Antagonists , Animals , CHO Cells , Cricetinae , Cricetulus , Drug Design , Guanosine 5'-O-(3-Thiotriphosphate)/antagonists & inhibitors , Humans , Molecular Conformation , Receptors, Opioid, delta/antagonists & inhibitors , Receptors, Opioid, kappa/antagonists & inhibitors , Receptors, Opioid, mu/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
The phenolic hydroxy group of opiate-derived ligands is of known importance for biological activity. We have developed a SAR study around LY255582 by comparing the effect of the hydroxy group in the 2- and 4-position of the phenyl ring. Also, we have proved that the 3-position of the phenyl ring is optimal for opioid activity. Furthermore, we have successfully replaced the hydroxy group in LY255582 by carbamate and carboxamide groups. The new analogs have high affinity for the opioid receptors comparable to the corresponding phenol. Carboxamide analog 12 has an improved metabolism profile and proved to be efficacious in in vivo studies.
Subject(s)
Narcotic Antagonists/chemical synthesis , Piperidines/chemical synthesis , Administration, Oral , Animals , Cyclohexanes , Drug Evaluation, Preclinical , Feeding Behavior/drug effects , Ligands , Liver/metabolism , Narcotic Antagonists/pharmacokinetics , Narcotic Antagonists/pharmacology , Pain/prevention & control , Phenols , Piperidines/pharmacokinetics , Piperidines/pharmacology , Radioligand Assay , Rats , Structure-Activity RelationshipABSTRACT
Differences in the anorectic activity of morphinan (e.g., naltrexone) and 3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (4PP) opioid receptor antagonists have been described. In an attempt to explain these differences, the influence of Na(+) on opioid binding affinity and functional activity of 4PP antagonists was compared to other opioid antagonists. The binding affinities of neutral antagonists were unaffected by the addition of Na(+), whereas that for the peptide, inverse agonist N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI174864) was increased. Similarly, the binding affinities of the 4PP antagonist (3R,4R)-1-((S)-3-hydroxy-3-cyclohexylpropyl)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidine (LY255582) and other 4PP antagonists were increased in the presence of Na(+) with the greatest effects at the delta opioid receptor followed by the mu and kappa opioid receptors, respectively. Similar to ICI174864, 4PP antagonists were found to inhibit basal GTPgamma[(35)S] binding at the delta opioid receptor indicating inverse agonist activity. A correlation was observed between the binding affinities in the presence of Na(+), the inverse agonist potency, and the anorectic potency of 4PP antagonists. These data suggest that 4PP antagonists differ from morphinan antagonists in their inverse agonist activity and suggest a relationship between inverse agonism and anorectic activity.
