title: Intrinsic activity and comparative molecular dynamics of buspirone analogues at the 5-HT(1A) receptors.
abstract: In CNS, the 5-hydroxytryptamine(1A) (5-HT(1A)) receptors exist in two different populations with different behavioural and physiological effects: (1) somatodendritic autoreceptors located pre-synaptically of 5-HT containing neurons and (2) receptors located post-synaptic to 5-HT containing neurons. Clinical studies have shown that 5-HT(1A) partial agonists have anxiolytic properties, while antagonists of pre-synaptical autoreceptors shorten the onset time of selective serotonin reuptake inhibitors (SSRIs). In the present study, the pre- and post-synaptic activity of structural analogues of buspirone was evaluated in animal models. A three dimensional model of the 5-HT(1A) receptor was used to study their interaction modes and helical displacements upon receptor binding. The predicted receptor-ligand interactions indicated similarities in the receptor binding modes for all buspirone analogues, and no clear relationship between receptor contact residues and activity at pre- and post-synaptic receptors. Comparative molecular dynamics (MD) simulations for 650ps indicated that pre-synaptic antagonistic behaviour is connected to large displacements of transmembrane helix (TMH) 7 upon binding, while pre-synaptic agonistic behaviour is connected to large displacements of TMH2 and small displacements of TMH7. Post-synaptic partial agonist behaviour is connected to large displacements of TMH4 and TMH5 upon binding, while post-synaptic antagonists only slightly displace these helices.
authors.affiliation: National Insititute of Public Health, Chelmska 30/34, 00-725 Warsaw, Poland.
authors.forename: Anna Agnieszka
authors.initials: AA
authors.lastname: Strzelczyk
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Jarończyk
authors.forename: Zdzislaw
authors.initials: Z
authors.lastname: Chilmonczyk
authors.forename: Aleksander Pawel
authors.initials: AP
authors.lastname: Mazurek
authors.forename: Ewa
authors.initials: E
authors.lastname: Chojnacka-Wójcik
authors.forename: Ingebrigt
authors.initials: I
authors.lastname: Sylte
mesh_terms: D000818:Animals; D001665:Binding Sites; D002065:Buspirone / Q000031:analogs & derivatives / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D002065:Buspirone