title: Synthesis and biological investigation of new equatorial (β) stereoisomers of 3-aminotropane arylamides with atypical antipsychotic profile.
abstract: A series of novel 3β-aminotropane derivatives containing a 2-naphthalene or a 2-quinoline moiety was synthesised and evaluated for their affinity for 5-HT1A, 5-HT2A and D2 receptors. Their affinity for the receptors was in the nanomolar to micromolar range. p-Substitution (6c, 6f, 6i, 6l, 6o), as well as substitution with chlorine atoms (6g, 6h, 6i), led to a significant increase in binding affinity for D2 receptors with compounds 6f (Ki=0.6nM), 6c and 6i (Ki=0.4nM), having the highest binding affinities. m-Substituted derivatives were the most promising ligands in terms of 5-HT2A receptor binding affinity whereas 2-quinoline derivatives (10a, 10b) displayed the highest affinity for 5-HT1AR and were the most selective ligands with Ki=62.7nM and Ki=30.5nM, respectively. Finally, the selected ligands 6b, 6d, 6e, 6g, 6h, 6k, 6n and 6o, with triple binding activity for the D2, 5-HT1A and 5-HT2A receptors, were subjected to in vivo tests, such as those for induced hypothermia, climbing behaviour and the head twitch response, in order to determine their pharmacological profile. The tested ligands presented neither agonist nor antagonist properties for the 5-HT1A receptors in the induced hypothermia and lower lip retraction (LLR) tests. All tested compounds displayed antagonistic activity against 5-HT2A, with 6n and 6o being the most active. Four (6b, 6k, 6n and 6o) out of eight tested compounds could be classified as D2 antagonists. Additionally, evaluation of metabolic stability was performed for selected ligands, and introduction of halogen atoms into the benzene ring of 6h, 6k, 6n and 6o improved their metabolic stability. The project resulted in the selection of the lead compounds 6n and 6o, which had antipsychotic profiles, combining dopamine D2-receptor and 5-HT2A antagonism and metabolic stability.
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02-097 Warsaw, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Stefanowicz
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02-097 Warsaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Słowiński
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02-097 Warsaw, Poland. Electronic address: martynawrobel.wum@gmail.com.
authors.forename: Martyna Zofia
authors.initials: MZ
authors.lastname: Wróbel
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02-097 Warsaw, Poland.
authors.forename: Franciszek
authors.initials: F
authors.lastname: Herold
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02-097 Warsaw, Poland.
authors.forename: Anna Edyta
authors.initials: AE
authors.lastname: Gomółka
authors.affiliation: Jagiellonian University Medical College, Department of Clinical Pharmacy, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Wesołowska
authors.affiliation: Jagiellonian University Medical College, Department of Clinical Pharmacy, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Jastrzębska-Więsek
authors.affiliation: Jagiellonian University Medical College, Department of Clinical Pharmacy, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Partyka
authors.affiliation: Isobolographic Analysis Laboratory, Institute of Rural Health, 2 Jaczewskiego Street, 20-950 Lublin, Poland.
authors.forename: Marta
authors.initials: M
authors.lastname: Andres-Mach
authors.affiliation: Department of Pathophysiology, Medical University, 8 Jaczewskiego Street, 20-090 Lublin, Poland; Department of Physiopathology, Institute of Rural Health, 2 Jaczewskiego Street, 20-950 Lublin, Poland.
authors.forename: Stanisław Jerzy
authors.initials: SJ
authors.lastname: Czuczwar
authors.affiliation: Isobolographic Analysis Laboratory, Institute of Rural Health, 2 Jaczewskiego Street, 20-950 Lublin, Poland; Department of Pathophysiology, Medical University, 8 Jaczewskiego Street, 20-090 Lublin, Poland.
authors.forename: Jarogniew Jacek
authors.initials: JJ
authors.lastname: Łuszczki
authors.affiliation: Isobolographic Analysis Laboratory, Institute of Rural Health, 2 Jaczewskiego Street, 20-950 Lublin, Poland.
authors.forename: Mirosław
authors.initials: M
authors.lastname: Zagaja
authors.affiliation: Department of Pharmacobiology, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Agata
authors.initials: A
authors.lastname: Siwek
authors.affiliation: Department of Pharmacobiology, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Nowak
authors.affiliation: Department of Pharmacobiology, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Żołnierek
authors.affiliation: Department of Pharmaceutical Chemistry, Medical University of Gdańsk, 107 Al. Gen. J. Hallera Street, 80-416 Gdańsk, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Bączek
authors.affiliation: Department of Pharmaceutical Chemistry, Medical University of Gdańsk, 107 Al. Gen. J. Hallera Street, 80-416 Gdańsk, Poland.
authors.forename: Szymon
authors.initials: S
authors.lastname: Ulenberg
authors.affiliation: Department of Pharmaceutical Chemistry, Medical University of Gdańsk, 107 Al. Gen. J. Hallera Street, 80-416 Gdańsk, Poland.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Belka
authors.affiliation: Department of Drug Technology and Pharmaceutical Biotechnology, Faculty of Pharmacy, Medical University of Warsaw, 1 Banacha Street, 02-097 Warsaw, Poland.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Turło
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001555:Benzene Derivatives / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D001555:Benzene Derivatives; D065127:Dopamine D2 Receptor Antagonists; D044402:Receptor, Serotonin, 5-HT2A; D017448:Receptors, Dopamine D2; D058830:Serotonin 5-HT2 Receptor Antagonists; D014326:Tropanes; D044282:Receptor, Serotonin, 5-HT1A
keywords: 3β-Aminotropane derivatives; 5-HT(1A); 5-HT(2A); Atypical antipsychotics; D(2); Dopamine receptor ligands