ABSTRACT
Opioidergic system plays an important role in controlling alcohol seeking behavior. We have previously shown that a quinoline compound, S4 (2-(2-methylquinolin-4-ylamino)-N-phenyl acetamide), having dual affinity for µ- and κ-opioid receptors, could successfully inhibit withdrawal symptoms in mice rendered dependent on morphine. Accordingly, in the present study, we sought to determine the potential of S4 in attenuating voluntary alcohol intake in alcohol-preferring (AP) mice and the mechanism thereof. The study was conducted in different mice strains initially screened for AP and alcohol-avoiding (AA) behavior. S4 was injected subcutaneously (20 mg/kg) to evaluate its efficacy in reducing voluntary alcohol consumption along with prevention of body weight loss during withdrawal from alcohol after discontinuation of the drug. The results showed that S4 significantly reduced the alcohol intake in AP mice and also in a dose dependent manner. Mechanistic studies on the post translational histone H3 modifications in brain of AP mice compared to the AA mice were determined. Compared to AA mice, histone H3 trimethylation at lys9 and its regulators, jumonji domain containing 2A and phosphorylated histones H3 at thr11 as well as the expression of 14-3-3 protein and phosphorylated histones H3 at ser28, were altered in the AP animals, most of which were restored post S4 treatment in the AP mice. Together, the present results suggest that S4 effectively blocked alcohol drinking behavior by restoring the altered epigenetic signature in the AP mice. The study provides a novel compound which could lead to developing effective drugs against alcoholism/alcohol abuse.
Subject(s)
Alcohol Deterrents/pharmacology , Alcohol Drinking , Histones/metabolism , Quinolines/pharmacology , 14-3-3 Proteins/metabolism , Animals , Male , Mice , Mice, Inbred BALB C , PhosphorylationABSTRACT
Some novel iboga-analogues consisting of benzofuran moiety and dehydroisoquinuclidine ring connected by -CH2-, (CH2)2 and (CH2)3 linkers have been synthesized with the view to develop potential antinociceptive drugs. The compounds 14 and 21 showed binding at the µ-opioid receptor (MOR), while the compound 11a exhibited dual affinities at both MOR and κ-opioid receptor (KOR). MAP kinase activation indicated all three compounds have opioid agonistic properties. The presence of a double bond and endo-methylcarboxylate group in the dehydroisoquinuclidine ring and the benzofuran and methylene spacer appeared to be essential for opioid receptor binding. Further studies demonstrated 11a caused significant antinociception in mice in the hot-plate test which was comparable to that produced by morphine. The compound 11a was also found to be nontremorigenic unlike various iboga congeners. This study identifies a new pharmacophore which may lead to the development of suitable substitute of morphine in the treatment of pain.
Subject(s)
Analgesics, Opioid/chemistry , Analgesics, Opioid/therapeutic use , Pain/drug therapy , Quinuclidines/chemistry , Quinuclidines/therapeutic use , Analgesics, Opioid/chemical synthesis , Analgesics, Opioid/pharmacology , Animals , Cell Line , Humans , Mice , Mice, Inbred BALB C , Morphine/therapeutic use , Quinuclidines/chemical synthesis , Quinuclidines/pharmacology , Receptors, Opioid, kappa/metabolism , Receptors, Opioid, mu/metabolism , Tabernaemontana/chemistry , Tremor/drug therapyABSTRACT
A short and high yield synthetic route to dibenz[b,f][1,5]oxazocines has been developed using Pd catalyzed intramolecular cycloamination reaction. Receptor binding assay using [125I]-dynorphin demonstrated that one of the derivative, 5b showed selective κ-opioidergic property.
