Synthesis and biological investigations of 3β-aminotropane arylamide derivatives with atypical antipsychotic profile

• Published in: Medicinal chemistry research Vol. 27; no. 8; pp. 1906 - 1928
• Main Authors: Stefanowicz, Jacek, Słowiński, Tomasz, Wróbel, Martyna Z., Ślifirski, Grzegorz, Dawidowski, Maciej, Stefanowicz, Zdzisława, Jastrzębska-Więsek, Magdalena, Partyka, Anna, Wesołowska, Anna, Turło, Jadwiga
• Format: Journal Article
• Language: English
• Published: New York Springer US 2018; Springer Nature B.V
• Subjects: Affinity; Amphetamines; Antidepressants; Antipsychotics; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Derivatives; Dizocilpine; In vivo methods and tests; Mice; Original Research; Pharmacology/Toxicology; Psychotropic drugs; Quinoline; Receptors; Serotonin S1 receptors; Serotonin S2 receptors; Tropane; 3β-aminotropane derivatives; Atypical antipsychotics; D; 5-HT; Dopamine receptor ligands; 5-HT1A, 5-HT2A, D2
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-018-2203-z

This work is a continuation of our previous research, concentrating this time on lead structure modification to increase the 5-HT 1A receptor affinity and water solubility of designed compounds. Therefore, the compounds synthesised within the present project included structural analogues of 3β-acylamine derivatives of tropane with the introduction of a methyl substituent in the benzyl ring and a 2-quinoline, 3-quinoline, or 6-quinoline moiety. A series of novel 3β - aminotropane derivatives was evaluated for their affinity for 5-HT 1A , 5-HT 2A , and D 2 receptors, which allowed for the identification of compounds 12e , 12i , and 19a as ligands with highest affinity for the tested receptors; they were then subjected to further evaluation in preliminary in vivo studies. Selected compounds 12i and 19a displayed antipsychotic properties in the d-amphetamine-induced and MK-801-induced hyperlocomotor activity test in mice. Moreover, compound 19a showed significant antidepressant-like activity in the forced swim test in mice.