title: Synthesis of dihydrofuroaporphine derivatives: identification of a potent and selective serotonin 5-HT 1A receptor agonist.
abstract: A series of new aporphine analogues were synthesized and pharmacologically evaluated. 11-Allyloxy-(17), 11-propargyloxy-(20), and dihydrofuro-(19) aporphines displayed the highest affinity at the 5-HT(1A) receptor with K(i) values of 12.0, 14.0, and 6.7 nM, respectively. The high binding potential of the diastereomeric mixture of aporphine 19 was found residing in the cis-diastereomer (cis-19). [(35)S]GTP gamma S function assays on 5-HT(1A) receptor indicated that aporphines 17 and 20 were partial agonists, while trans-19 behaved as a high efficacy full antagonist and cis-19 was a full agonist. The agonistic property of cis-19 at the 5-HT(1A) receptor was further confirmed in vitro and in vivo. This compound may be useful as a potential treatment for anxiety.
authors.affiliation: Synthetic Organic & Medicinal Chemistry Laboratory (SOMCL), Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zhili
authors.initials: Z
authors.lastname: Liu
authors.forename: Hai
authors.initials: H
authors.lastname: Zhang
authors.forename: Na
authors.initials: N
authors.lastname: Ye
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: QianQian
authors.initials: Q
authors.lastname: Wu
authors.forename: Peihua
authors.initials: P
authors.lastname: Sun
authors.forename: Linyong
authors.initials: L
authors.lastname: Li
authors.forename: Xuechu
authors.initials: X
authors.lastname: Zhen
authors.forename: Ao
authors.initials: A
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001060:Aporphines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C547677:11-allyloxy-N-methylaporphine; C547676:11-propargyloxy-N-methylaporphine; D001060:Aporphines; C547675:N-methyl-2'-methyl-2',3'-dihydrofuro(m)aporphine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; D016244:Guanosine 5'-O-(3-Thiotriphosphate)