title: 2-[(2,3-dihydro-1H-indol-1-yl)methyl]melatonin analogues: a novel class of MT2-selective melatonin receptor antagonists.
abstract: A novel series of 2-[(2,3-dihydro-1H-indol-1-yl)methyl]melatonin analogues has been prepared to probe the steric and electronic properties of the binding pocket of the MT(2) receptor accommodating the "out-of-plane" substituent of MT(2)-selective antagonists. The acetamide (6b) bearing an usubstituted indoline moiety displayed an excellent binding affinity and selectivity toward the MT(2)-subtype (MT(2), K(i) = 1 nM; MT(1), K(i) = 115 nM), behaving as a competitive antagonist. 5-Me, 5-OMe, 5-Br, 6-NH(2), and 6-NO(2) substitution of the indoline moiety reduced both MT(2) affinity and selectivity, indicating that hydrophobic interactions play a decisive role in binding the out-of-plane substituent. The cyclobutanecarboxamide (6e) showed a biphasic binding pattern at MT(2) receptors, indicating the presence of two MT(2) binding sites, a high affinity (K(i) = 1 pM) and a low affinity (K(i) = 148 nM), while MT(1) binding affinity was very low (K(i) = 1.4 microM). Functional analysis of 6e revealed it to be an antagonist at MT(1) receptors and a partial agonist, at best, at MT(2) receptors.
authors.affiliation: Institute of Pharmacy and Food Chemistry, Pharmaceutical Chemistry, University of Würzburg, Am Hubland, 97074 Würzburg, Germany. zlotos@pzlc.uni-wuerzburg.de
authors.forename: Darius P
authors.initials: DP
authors.lastname: Zlotos
authors.forename: Mohamed I
authors.initials: MI
authors.lastname: Attia
authors.forename: Justin
authors.initials: J
authors.lastname: Julius
authors.forename: Shalini
authors.initials: S
authors.lastname: Sethi
authors.forename: Paula A
authors.initials: PA
authors.lastname: Witt-Enderby
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008550:Melatonin / Q000031:analogs & derivatives*; D044094:Receptors, Melatonin / Q000819:agonists / Q000037:antagonists & inhibitors*
chemical_list: D007211:Indoles; D044094:Receptors, Melatonin; D008550:Melatonin