title: Temperature dependence of the affinity enhancement of selective adenosine A1 receptor agonism: a thermodynamic analysis.
abstract: The 2-amino-benzoylthiophene derivatives LUF 5468 [(2-amino-4-ethyl-5-methyl-3-thienyl)[3-(trifluoromethyl)phenyl]methanone] and LUF 5484 [(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(3,4-dichlorophenyl)methanone] have been shown to allosterically enhance the adenosine A(1) receptor agonist binding. We report a thermodynamic analysis of the agonist affinity obtained at human adenosine A(1) receptors, in the presence and absence of LUF 5468 and LUF 5484. Moreover, an analysis of the temperature dependence for association and dissociation rates of N(6)-cyclohexyladenosine (CHA) binding was performed in the absence and presence of LUF 5484. Thermodynamic data were obtained by affinity measurements performed at different temperatures followed by van't Hoff analysis. The results indicate that the agonist binding is always totally entropy-driven, and that the modulators contribute to decrease the deltaG(o), deltaH(o) and deltaS(o) values. It is concluded that the enhancers are able to increase the non-bonded interactions of the binding site with agonists as CHA, N(6)-cyclopentlyladenosine (CPA), 2'-methyl-N(6)-cyclopentyladenosine (MeCPA) and 2-chloro-2'methyl-N(6)-cyclopentyladenosine (MeCCPA).
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Ferrara University, via Fossato di Mortara 19, 44100 Ferrara, Italy. dla@dns.unife.it
authors.forename: Alessandro
authors.initials: A
authors.lastname: Dalpiaz
authors.forename: Barbara
authors.initials: B
authors.lastname: Pavan
authors.forename: Françoise Ngo
authors.initials: FN
authors.lastname: Ngos
authors.forename: Palmarisa
authors.initials: P
authors.lastname: Franchetti
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: IJzerman
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006801:Humans; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013696:Temperature; D013816:Thermodynamics
chemical_list: D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1