2013 |
Sotomayor-Zarate, R; Gysling, K; Busto, U E; Cassels, B K; Tampier, L; Quintanilla, M E Varenicline and Cytisine: Two Nicotinic Acetylcholine Receptor Ligands Reduce Ethanol Intake in University of Chile Bibulous Rats Artículo de revista Psychopharmacology, 227 (2), pp. 287-298, 2013, ISSN: 0033-3158. Resumen | Enlaces | BibTeX | Etiquetas: agonist, alpha-4-beta-2, beta-2 clinical-efficacy, consumption, cytisine, dependence ethanol high-alcohol-drinking modulation, partial preference, rats, sazetidine-a, smoking-cessation, subunit, uchb varenicline @article{RN127, title = {Varenicline and Cytisine: Two Nicotinic Acetylcholine Receptor Ligands Reduce Ethanol Intake in University of Chile Bibulous Rats}, author = { R. Sotomayor-Zarate and K. Gysling and U.E. Busto and B.K. Cassels and L. Tampier and M.E. Quintanilla}, url = {/brokenurl#<Go to ISI>://WOS:000318310400010}, doi = {10.1007/s00213-013-2974-3}, issn = {0033-3158}, year = {2013}, date = {2013-01-01}, journal = {Psychopharmacology}, volume = {227}, number = {2}, pages = {287-298}, abstract = {Neuronal nicotinic acetylcholine receptors (nAChRs) are pharmacological targets that have recently been implicated in the reinforcing effects of many drugs of abuse, including ethanol. Varenicline and cytisine are nAChR partial agonists in clinical use as smoking cessation aids. However, their efficacies to reduce alcohol consumption have not been fully studied., This study aims to compare the effects of varenicline and cytisine on ethanol consumption by rats bred for many generations as high ethanol drinkers (UChB)., Repeated dosing (0.5 or 1.0 mg/kg/day i.p.) of varenicline or cytisine, for three consecutive days, to male UChB rats pre-exposed to 10 % (v/v) ethanol and water 24 h/day for 4 weeks, significantly reduced alcohol intake and preference of ethanol over water during 1- and 24-h ethanol access periods. This effect was specific for ethanol intake and was not observed for 0.2 % saccharin or water consumption. Varenicline appears to be more effective than cytisine, probably due to its more favorable pharmacokinetic and pharmacodynamic properties. Long-term use of both nAChRs ligands for more than 8-10 days induced tolerance to their effects on ethanol consumption., This preclinical study in UChB rats demonstrated that both varenicline and cytisine reduce alcohol intake, with varenicline producing a greater and longer-lasting reduction than cytisine. However, dose adjustment will have to be considered as a possible way to counter tolerance arising after continued use.}, keywords = {agonist, alpha-4-beta-2, beta-2 clinical-efficacy, consumption, cytisine, dependence ethanol high-alcohol-drinking modulation, partial preference, rats, sazetidine-a, smoking-cessation, subunit, uchb varenicline}, pubstate = {published}, tppubtype = {article} } Neuronal nicotinic acetylcholine receptors (nAChRs) are pharmacological targets that have recently been implicated in the reinforcing effects of many drugs of abuse, including ethanol. Varenicline and cytisine are nAChR partial agonists in clinical use as smoking cessation aids. However, their efficacies to reduce alcohol consumption have not been fully studied., This study aims to compare the effects of varenicline and cytisine on ethanol consumption by rats bred for many generations as high ethanol drinkers (UChB)., Repeated dosing (0.5 or 1.0 mg/kg/day i.p.) of varenicline or cytisine, for three consecutive days, to male UChB rats pre-exposed to 10 % (v/v) ethanol and water 24 h/day for 4 weeks, significantly reduced alcohol intake and preference of ethanol over water during 1- and 24-h ethanol access periods. This effect was specific for ethanol intake and was not observed for 0.2 % saccharin or water consumption. Varenicline appears to be more effective than cytisine, probably due to its more favorable pharmacokinetic and pharmacodynamic properties. Long-term use of both nAChRs ligands for more than 8-10 days induced tolerance to their effects on ethanol consumption., This preclinical study in UChB rats demonstrated that both varenicline and cytisine reduce alcohol intake, with varenicline producing a greater and longer-lasting reduction than cytisine. However, dose adjustment will have to be considered as a possible way to counter tolerance arising after continued use. |
Faundez-Parraguez, M; Farias-Rabelo, N; González-Gutierrez, J P; Etcheverry-Berrios, A; Alzate-Morales, J; Adasme-Carreno, F; Varas, R; Bermudez, I; Iturriaga-Vasquez, P Neonicotinic Analogues: Selective Antagonists for Alpha 4 Beta 2 Nicotinic Acetylcholine Receptors Artículo de revista Bioorganic & Medicinal Chemistry, 21 (10), pp. 2687-2694, 2013, ISSN: 0968-0896. Resumen | Enlaces | BibTeX | Etiquetas: agonists, and antagonism, beta-2 binding, cytisine, docking functional modulators, nicotinic receptors, relationships, sensitivity, structure-activity subunit @article{RN130, title = {Neonicotinic Analogues: Selective Antagonists for Alpha 4 Beta 2 Nicotinic Acetylcholine Receptors}, author = { M. Faundez-Parraguez and N. Farias-Rabelo and J.P. Gonz\'{a}lez-Gutierrez and A. Etcheverry-Berrios and J. Alzate-Morales and F. Adasme-Carreno and R. Varas and I. Bermudez and P. Iturriaga-Vasquez}, url = {/brokenurl#<Go to ISI>://WOS:000318318700003}, doi = {10.1016/j.bmc.2013.03.024}, issn = {0968-0896}, year = {2013}, date = {2013-01-01}, journal = {Bioorganic & Medicinal Chemistry}, volume = {21}, number = {10}, pages = {2687-2694}, publisher = {2013 Elsevier Ltd.}, abstract = {Nicotine is an agonist of nicotinic acetylcholine receptors (nAChRs) that has been extensively used as a template for the synthesis of alpha 4 beta 2-preferring nAChRs. Here, we used the N-methyl-pyrrolidine moiety of nicotine to design and synthesise novel alpha 4 beta 2-preferring neonicotinic ligands. We increased the distance between the basic nitrogen and aromatic group of nicotine by introducing an ester functionality that also mimics acetylcholine (Fig. 2). Additionally, we introduced a benzyloxy group linked to the benzoyl moiety. Although the neonicotinic compounds fully inhibited binding of both [alpha-I-125]bungarotoxin to human alpha 7 nAChRs and [H-3]cytisine to human alpha 4 beta 2 nAChRs, they were markedly more potent at displacing radioligand binding to human alpha 4 beta 2 nAChRs than to alpha 7 nAChRs. Functional assays showed that the neonicotinic compounds behave as antagonists at alpha 4 beta 2 and alpha 4 beta 2 alpha 5 nAChRs. Substitutions on the aromatic ring of the compounds produced compounds that displayed marked selectivity for alpha 4 beta 2 or alpha 4 beta 2 alpha 5 nAChRs. Docking of the compounds on homology models of the agonist binding site at the alpha 4/beta 2 subunit interfaces of alpha 4 beta 2 nAChRs suggested the compounds inhibit function of this nAChR type by binding the agonist binding site.}, keywords = {agonists, and antagonism, beta-2 binding, cytisine, docking functional modulators, nicotinic receptors, relationships, sensitivity, structure-activity subunit}, pubstate = {published}, tppubtype = {article} } Nicotine is an agonist of nicotinic acetylcholine receptors (nAChRs) that has been extensively used as a template for the synthesis of alpha 4 beta 2-preferring nAChRs. Here, we used the N-methyl-pyrrolidine moiety of nicotine to design and synthesise novel alpha 4 beta 2-preferring neonicotinic ligands. We increased the distance between the basic nitrogen and aromatic group of nicotine by introducing an ester functionality that also mimics acetylcholine (Fig. 2). Additionally, we introduced a benzyloxy group linked to the benzoyl moiety. Although the neonicotinic compounds fully inhibited binding of both [alpha-I-125]bungarotoxin to human alpha 7 nAChRs and [H-3]cytisine to human alpha 4 beta 2 nAChRs, they were markedly more potent at displacing radioligand binding to human alpha 4 beta 2 nAChRs than to alpha 7 nAChRs. Functional assays showed that the neonicotinic compounds behave as antagonists at alpha 4 beta 2 and alpha 4 beta 2 alpha 5 nAChRs. Substitutions on the aromatic ring of the compounds produced compounds that displayed marked selectivity for alpha 4 beta 2 or alpha 4 beta 2 alpha 5 nAChRs. Docking of the compounds on homology models of the agonist binding site at the alpha 4/beta 2 subunit interfaces of alpha 4 beta 2 nAChRs suggested the compounds inhibit function of this nAChR type by binding the agonist binding site. |
2013 |
Varenicline and Cytisine: Two Nicotinic Acetylcholine Receptor Ligands Reduce Ethanol Intake in University of Chile Bibulous Rats Artículo de revista Psychopharmacology, 227 (2), pp. 287-298, 2013, ISSN: 0033-3158. |
Neonicotinic Analogues: Selective Antagonists for Alpha 4 Beta 2 Nicotinic Acetylcholine Receptors Artículo de revista Bioorganic & Medicinal Chemistry, 21 (10), pp. 2687-2694, 2013, ISSN: 0968-0896. |