One approach toward new antidepressants with better clinical parameters is the synthesis of compounds with dual SERT inhibitor/5-HT_1A activity [1]. Among many concepts in this field, the idea of incorporating a 5-HT_1A antagonist component into the structure of an SSRI is thought to be the most advantageous. However, there is a concern that the use of 5-HT_1A receptor antagonist without discriminating between its pre- and postsynaptic activity could cancel the benefits of enhancing presinaptically the 5-HT function. Therefore an alternative method is the design of compounds with dual 5-HT reuptake blockade/5-HT_1A receptor agonist action, which could desensitize presynaptic 5-HT_1A receptors and postinaptically enhance serotonin transmission [2-4].
The aim of this work was the design, synthesis and biological evaluation of new compounds with dual 5-HT_1A and 5-HT-T affinity.
The structures of the new compounds were confirmed by ¹H and ¹³C NMR spectral data as well as by C, H, N analysis.
Target compounds were tested for their affinity for 5-HT_1A receptor and 5-HT reuptake inhibition using radioligand binding assay. Compounds 7j and 7k revealed very high affinity to 5-HT_1A and 5-HT-T receptors (7j K_{i 5-HT1A}= 4,8nM / K_{i 5-HT-T}= 0,7nM, 7k K_{i 5-HT1A}= 5,8nM / K_{i 5-HT-T}= 0,3nM). Other ligands showed high to moderate affinities.
Compounds 7d (20mg/kg), 7g (10mg/kg), 7i (20mg/kg), 7j (20mg/kg) and 7k (20mg/kg) were found to be presynaptic 5-HT_1A receptor agonists in induced hypothermia test in mice.
Compounds 7g (20mg/kg), 7i (20mg/kg) and 7j (10mg/kg) revealed their postsynaptic 5-HT_1A agonist activity in forced swimming test in mice.

R_1, R_2, R₃: 7a: H, H, OCH₃; 7b: H, OCH₃, H; 7c: H, OCH₃, OCH₃; 7d: H, Cl, H; 7e: H, Cl, OCH₃; 7f: F, H, OCH₃; 7g: H, F, H; 7h: H, F, OCH₃; 7i: H, H, H; 7j: F, H, H; 7k: H, CH₃, H; 7l: H, CH₃, OCH₃;

• Legal notice:
  

  Copyright (c) Pielaszek Research, all rights reserved.
  The above materials, including auxiliary resources, are subject to Publisher's copyright and the Author(s) intellectual rights. Without limiting Author(s) rights under respective Copyright Transfer Agreement, no part of the above documents may be reproduced without the express written permission of Pielaszek Research, the Publisher. Express permission from the Author(s) is required to use the above materials for academic purposes, such as lectures or scientific presentations.
  In every case, proper references including Author(s) name(s) and URL of this webpage: https://science24.com/paper/14697 must be provided.

1. Alkyl-nitroquipazine derivatives as serotonin transporter and 5-HT_1A receptor ligands
2. Mannich bases, 5-arylimidazolidine-2,4-dione derivatives with arylpiperazine moiety, as 5-HT_1A receptor ligands with serotonin transporter affinity
3. Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT_1A activity. Part 2.
4. Synthesis of novel pyrido[1,2-c]pyrimidine derivatives as selective ligands for 5-HT_1A receptors
5. SYNTHESIS AND AFFINITY FOR SEROTONIN RECEPTOR 5HT_1A AND SEROTONIN TRANSPORTER OF SOME 6-NITROQUIPAZINE ANALOGUES.
6. SYNTHESIS OF NEW 4,5-DIHYDRO- 3aH-IMIDAZO[1,5-a]QUINOLINE DERIVATIVES AS 5-HT_1A SEROTONIN RECEPTOR LIGANDS.
7. NEW PERHYDRO-PYRROLO[1,2-a]PYRAZINE DERIVATIVES WITH AN ARYLPIPERAZINE MOIETY AS LIGANDS FOR 5-HT_1A RECEPTOR.
8. ARYLPIPERAZINYLBUTYL DERIVATIVES OF SOME IMIDAZO[2,1-f]THEOPHYLLINE AS CNS RECEPTOR LIGANDS.
9. NOVEL 4-ARYL-2H-PYRIDO[1,2-c]PYRIMI- DINES WITH 5-HT-TRANSPORTER AND 5-HT_1A AFFINITY
10. SYNTHESIS OF 8-FURFURYLTROPANE BENZAMIDE DERIVATIVES WITH POTENTIAL ANTIPSYCHOTIC ACTIVITY
11. SYNTHESIS AND PHARMACOLOGICAL ACTIVITY OF NEW 5,5-DISUBSTITUTED HYDANTOINS
12. SYNTHESIS, IN VITRO AND IN VIVO ACTIVITY OF THE ARYLPIPERAZINYLPROPYL DERIVATIVES OF THE IMIDAZO[2,1-f]THEO- PHYLLINE