title: (R)-11-hydroxy- and (R)-11-hydroxy-10-methylaporphine: synthesis, pharmacology, and modeling of D2A and 5-HT1A receptor interactions.
abstract: (R)-11-Hydroxyaporphine (2) and (R)-11-hydroxy-10-methylaporphine (3) were synthesized from natural morphine by using new, short, and efficient synthetic sequences. The dopaminergic and serotonergic effects of 2 and 3 were evaluated by use of in vitro and in vivo test systems. The results indicate that 3 is a potent, selective, and efficacious 5-HT1A receptor agonist. In contrast, 2 is a partial 5-HT1A receptor agonist of low potency which has affinity also for central D1 and D2A receptors. The differences in pharmacological profiles were rationalized by modeling of ligand-receptor interactions using homology-based receptor models of the 5-HT1A and D2A receptor binding site. The selective and pronounced serotonergic effects of 3 appear to be due to the C10-methyl group, which is accommodated by a lipophilic pocket in the 5-HT1A receptor. In contrast, the C10-methyl group of 3 is not accommodated by the binding site model of the D2A receptor.
authors.affiliation: Uppsala University, Uppsala Biomedical Centre, Sweden.
authors.forename: M H
authors.initials: MH
authors.lastname: Hedberg
authors.forename: A M
authors.initials: AM
authors.lastname: Johansson
authors.forename: G
authors.initials: G
authors.lastname: Nordvall
authors.forename: A
authors.initials: A
authors.lastname: Yliniemelä
authors.forename: H B
authors.initials: HB
authors.lastname: Li
authors.forename: A R
authors.initials: AR
authors.lastname: Martin
authors.forename: S
authors.initials: S
authors.lastname: Hjorth
authors.forename: L
authors.initials: L
authors.lastname: Unelius
authors.forename: S
authors.initials: S
authors.lastname: Sundell
authors.forename: U
authors.initials: U
authors.lastname: Hacksell
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001060:Aporphines / Q000138:chemical synthesis / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D003196:Computer Graphics; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006801:Humans; D008297:Male; D017551:Microdialysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D001060:Aporphines; D017448:Receptors, Dopamine D2; D017366:Serotonin Receptor Agonists; C054813:PM 1000; D005576:Colforsin; C007984:11-hydroxyaporphine; D000262:Adenylyl Cyclases