Discovery of orexant and anorexant agents with indazole scaffold endowed with peripheral antiedema activity

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dc.authorid0000-0001-5926-6194
dc.authorid0000-0001-6548-7823
dc.authorid0000-0002-7242-4860
dc.contributor.authorDimmito, Marilisa P.
dc.contributor.authorStefanucci, Azzurra
dc.contributor.authorPieretti, Stefano
dc.contributor.authorMinosi, Paola
dc.contributor.authorDvoracsko, Szabolcs
dc.contributor.authorTomboly, Csaba
dc.contributor.authorZengin, Gökhan
dc.contributor.authorMollica, Adriano
dc.date.accessioned2020-03-26T20:13:27Z
dc.date.available2020-03-26T20:13:27Z
dc.date.issued2019
dc.departmentSelçuk Üniversitesi, Fen Fakültesi, Biyoloji Bölümüen_US
dc.description.abstractThe endocannabinoid system represents an integrated neuronal network involved in the control of several organisms' functions, such as feeding behavior. A series of hybrids of 5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (mimonabant), a well-known inverse agonist of the type-1 cannabinoid receptor (CB1), once used as an antiobesity drug, and the N-(2S)-substitutes of 1-[(4-fluorophenyl)methyl]indazole-3-carboxamide with 1-amino-3-methyl-1-oxobutane (AB-Fubinaca), 1-amino-3,3-dimethyl-1-oxobutane (ADB-Fubinaca), and 3-methylbutanoate (AMB-Fubinaca), endowed with potent agonistic activity towards cannabinoid receptors CB1 and CB2 were in solution as C-terminal amides, acids, methyl esters and N-methyl amides. These compounds have been studied by binding assays to cannabinoid receptors and by functional receptor assays, using rat brain membranes in vitro. The most active among them as an agonist, (S)-1-(2,4-dichlorobenzyl)-N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-1H-indazole-3-carboxamide (LONI11), and an antagonist, (S)-2-(1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxamido)-3-methylbutanoic acid (LONI4), were tested in vivo in mic, to evaluate their ability to stimulate or suppress feeding behavior after intraperitoneal (i.p.) administration. For a LONI11 formalin test and a tail flick test after an administration by the subcutaneous (s.c.) and intracerebroventricular (i.c.v.) routes, respectively, were also carried out in vivo in mice to investigate the antinociceptive property at the central and peripheral levesl. We observed a significant orexant effect for LONI11 and an intense anorexant effect for (S)-methyl 2-(1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxamido)-3,3-dimethylbutanoate (LONI2) and LONI4. In zymosan-induced edema and hyperalgesia, LONI11 reduced the percent of paw volume increase and paw latency after s.c. administration, also suggesting a possible peripheral anti-inflammatory activity.en_US
dc.identifier.citationDimmito, M. P., Stefanucci, A., Pieretti, S., Minosi, P., Dvorácskó, S., Tömböly, C., Zengin, G., Mollica, A. (2019). Discovery of Orexant and Anorexant Agents with Indazole Scaffold Endowed with Peripheral Antiedema Activity. Biomolecules, 9(9), 492.
dc.identifier.doi10.3390/biom9090492en_US
dc.identifier.issn2218-273Xen_US
dc.identifier.issue9en_US
dc.identifier.pmid31527522en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://dx.doi.org/10.3390/biom9090492
dc.identifier.urihttps://hdl.handle.net/20.500.12395/37698
dc.identifier.volume9en_US
dc.identifier.wosWOS:000489102800104en_US
dc.identifier.wosqualityQ2en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.institutionauthorZengin, Gökhan
dc.language.isoenen_US
dc.publisherMDPIen_US
dc.relation.ispartofBIOMOLECULESen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.selcuk20240510_oaigen_US
dc.subjectCannabinoid receptoren_US
dc.subjectRimonabanten_US
dc.subjectFood intakeen_US
dc.subjectAnorexant agenten_US
dc.subjectPeripheral antiedema activityen_US
dc.titleDiscovery of orexant and anorexant agents with indazole scaffold endowed with peripheral antiedema activityen_US
dc.typeArticleen_US

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