title: Systematic in vivo screening of a series of 1-propyl-4-arylpiperidines against dopaminergic and serotonergic properties in rat brain: a scaffold-jumping approach.
abstract: A series of 1-propyl-4-arylpiperidines were synthesized and their effects on the dopaminergic and serotonergic systems tested in vivo and in vitro. Scaffold jumping among five- and six-membered bicyclic aryl rings attached to the piperidine ring had a marked impact on these effects. Potent and selective dopamine D(2) receptor antagonists were generated from 3-indoles, 3-benzoisoxazoles, 3-benzimidazol-2-one, and 3-benzothiophenes. In contrast, 3-benzofuran was a potent and selective inhibitor of monoamine oxidase (MAO) A. The effects of the synthesized compounds on 3,4-dihydroxyphenylacetic acid (DOPAC) levels correlated very well with their affinity for dopamine D(2) receptors and MAO A. In the 4-arylpiperidine series, the most promising compound for development was the 6-chloro-3-(1-propyl-4-piperidyl)-1H-benzimidazol-2-one (19), which displayed typical dopamine D(2) receptor antagonist properties in vivo but produced only a partial reduction on spontaneous locomotor activity. This indicates that the compound may have a lower propensity to induce parkinsonism in patients.
authors.affiliation: NeuroSearch Sweden AB, Arvid Wallgrens Backe 20, SE-413 46 Gothenburg, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Mattsson
authors.forename: Theresa
authors.initials: T
authors.lastname: Andreasson
authors.forename: Nicholas
authors.initials: N
authors.lastname: Waters
authors.forename: Clas
authors.initials: C
authors.lastname: Sonesson
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D008124:Locomotion / Q000187:drug effects; D015394:Molecular Structure; D011618:Psychotic Disorders / Q000188:drug therapy; D051381:Rats; D012701:Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D015259:Dopamine Agents; D065127:Dopamine D2 Receptor Antagonists; D017366:Serotonin Receptor Agonists; D012701:Serotonin; D004298:Dopamine