title: Synthesis and biological investigation of potential atypical antipsychotics with a tropane core. Part 1.
abstract: The synthesis, structure, in vitro and in vivo pharmacological activities of 3β-acylamine derivatives of tropane (4a-n, 5a-g, 6a,b, 8a-c) are described. Among the investigated compounds, several displayed very high (in nM) affinity for the monoamine receptors 5-HT(1A), 5-HT(2A,) and D(2). The most interesting agent 6b revealed very high affinity for the 5-HT(2A) and D(2) receptors and high affinity for the 5-HT(1A) receptor. The in vivo head twitch model was used to demonstrate antagonism of the 5-HT(2A) receptor subtype by this compound. In another test, 6b caused hypothermia in mice, which was not attenuated by WAY 100635. In the climbing test, the compound did not significantly modify climbing behaviour following apomorphine administration. Moreover, 6b significantly reduced locomotor activity in mice. Molecular docking studies using a homology model of the 5-HT(1A) receptor revealed a significant role of the N-8 atom of the tropane core in stabilising the ligand-receptor complex due to strong hydrogen bonding with Asp116 located in the TMH 3 helix. Analogically, in a homology model of the 5-HT(2A) receptor, the N-8 atom formed a hydrogen bond with Gly369. In another homology model of the D(2) receptor, strong hydrogen bonding of the amide moiety in the 3β position of the tropane nucleus with Asp85 was observed. Compound 6b displayed a favourable Meltzer index (1.21) which is a feature of atypical antipsychotic agents.
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Słowiński
authors.forename: Jacek
authors.initials: J
authors.lastname: Stefanowicz
authors.forename: Maciej
authors.initials: M
authors.lastname: Dawidowski
authors.forename: Jerzy
authors.initials: J
authors.lastname: Kleps
authors.forename: Stanisław
authors.initials: S
authors.lastname: Czuczwar
authors.forename: Marta
authors.initials: M
authors.lastname: Andres-Mach
authors.forename: Jarogniew J
authors.initials: JJ
authors.lastname: Łuszczki
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nowak
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Stachowicz
authors.forename: Bernadeta
authors.initials: B
authors.lastname: Szewczyk
authors.forename: Anna
authors.initials: A
authors.lastname: Sławińska
authors.forename: Aleksander P
authors.initials: AP
authors.lastname: Mazurek
authors.forename: Andrzej
authors.initials: A
authors.lastname: Mazurek
authors.forename: Franciszek
authors.initials: F
authors.lastname: Pluciński
authors.forename: Irena
authors.initials: I
authors.lastname: Wolska
authors.forename: Franciszek
authors.initials: F
authors.lastname: Herold
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008958:Models, Molecular; D011869:Radioligand Assay; D051381:Rats; D017981:Receptors, Neurotransmitter / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000737:chemistry*
chemical_list: D014150:Antipsychotic Agents; D017981:Receptors, Neurotransmitter; D014326:Tropanes