title: Synthesis and pharmacological evaluation of 1,2,3,4-tetrahydropyrazino[1,2-a]indole and 2-[(phenylmethylamino)methyl]-1H-indole analogues as novel melatoninergic ligands.
abstract: Two novel series of melatonin-derived compounds have been synthesized and pharmacologically evaluated at the MT(1) and MT(2) subtypes of melatonin receptors. Compounds 12b-c are non-selective high-affinity MT(1) and MT(2) receptor ligands (K(i)=7-11 nM). Compound 12b had little intrinsic activity at the MT(1) receptor and no intrinsic activity at the MT(2) receptor. Compound 20d displayed the highest MT(2) binding affinity (K(i)=2 nM) and moderate selectivity toward the MT(2) subtype (K(i) MT(1)/MT(2) ratio=8) behaving as MT(2) antagonist and MT(1) agonist (IC(50)=112 pM). The findings help define SARs around the positions 1 and 2 of melatonin with respect to binding affinity, MT(2) selectivity, and intrinsic activity.
authors.affiliation: Institute of Pharmacy and Food Chemistry, Pharmaceutical Chemistry, University of Würzburg, Am Hubland, Würzburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Markl
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
authors.forename: Darius P
authors.initials: DP
authors.lastname: Zlotos
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008024:Ligands; D008550:Melatonin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding; D044122:Receptor, Melatonin, MT1 / Q000378:metabolism*; D044123:Receptor, Melatonin, MT2 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D008550:Melatonin