title: Synthesis, biological evaluation, and quantitative receptor docking simulations of 2-[(acylamino)ethyl]-1,4-benzodiazepines as novel tifluadom-like ligands with high affinity and selectivity for kappa-opioid receptors.
abstract: The synthesis and biological evaluation of a series of 2-substituted 5-phenyl-1,4-benzodiazepines, structurally related to tifluadom (5), the only benzodiazepine that acts simultaneously as a kappa-opioid agonist and a cholecystokinin-A (CCK-A) antagonist, are reported. The radioligand binding models used in these studies were [(125)I](BH)-CCK-8 in rat pancreas (CCK-A), [(3)H]-(MENLE(28,31))-cck-8 in guinea pig cerebral cortex (CCK-B), and [(3)H]U-69593 (kappa(1)), [(3)H]DAMGO (mu), and [(3)H]DADLE (delta) in guinea pig brain. All the title compounds were devoid of significant affinity for both CCK-A and CCK-B receptors, while some of them bound with nanomolar affinity and high selectivity for kappa-opioid receptors. In particular, the 2-thienyl derivative 7A(X = H) with a K(i) = 0.50 nM represents a clear improvement with respect to tifluadom, showing a comparable potency but higher selectivity. The application of computational simulations and linear regression analysis techniques to the complexes between guinea pig kappa (kappa(1))-receptor and the title compounds allowed the identification of the structural determinants for recognition and quantitative elucidation of the structure-affinity relationships in this class of receptors.
authors.affiliation: Dipartimento Farmaco Chimico Tecnologico, Universitá di Siena, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Cappelli
authors.forename: M
authors.initials: M
authors.lastname: Anzini
authors.forename: S
authors.initials: S
authors.lastname: Vomero
authors.forename: M C
authors.initials: MC
authors.lastname: Menziani
authors.forename: P G
authors.initials: PG
authors.lastname: De Benedetti
authors.forename: M
authors.initials: M
authors.lastname: Sbacchi
authors.forename: G D
authors.initials: GD
authors.lastname: Clarke
authors.forename: L
authors.initials: L
authors.lastname: Mennuni
mesh_terms: D000595:Amino Acid Sequence; D000700:Analgesics / Q000378:metabolism; D000818:Animals; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D003196:Computer Graphics; D017124:Conserved Sequence; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016308:Enkephalin, Leucine-2-Alanine / Q000378:metabolism; D004745:Enkephalins / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010179:Pancreas / Q000378:metabolism; D011487:Protein Conformation; D011869:Radioligand Assay; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000737:chemistry / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000819:agonists* / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D012844:Sincalide / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D004745:Enkephalins; D008024:Ligands; D011949:Receptors, Cholecystokinin; D017473:Receptors, Opioid, kappa; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D001569:Benzodiazepines; D016308:Enkephalin, Leucine-2-Alanine; D012844:Sincalide