The Synthesis and Absolute Configuration of Enantiomeric Pure (R)- and (S)-3-(piperidin-3-yl)-1H-Indole Derivatives.

This article describes the synthesis of new chiral 3-(piperidin-3-yl)-1H-indole derivatives (R)-10a-c and (S)-11a-c from the corresponding diastereomers: (3R, 2R) and (3S, 2R)-2-[3-(1H-indol-3-yl)-1-piperidyl]-2-phenyl-acetamides (3R, 2R)-4a, (3R, 2R)-6b, (3R, 2R)-8c and (3S, 2R)-5a, (3S, 2R)-7b, (3S, 2R)-9c. Diastereomers were obtained by N-alkylation of derivatives of racemic 3-(piperidin-3-yl)-1H-indoles 1a-c using (S)-2-(4-toluenesulfonyloxy)-phenylacetic amide (S)-II. The same method was applied to obtain (3R, 2S)-methyl-2-[3-(1H-indole-3-yl)-1-piperidyl]-2-phenylacetate (3R, 2S)-2a and (3S, 2S)-methyl-2-[3-(1H-indole-3-yl)-1-piperidyl]-2-phenylacetate (3S, 2S)-3a diastereomers by treating amine 1a with (R)-2-(4-toluenesulfonyloxy)-phenylacetic acid methylester (R)-I. Systematic studies via single crystal X-ray crystallography were used to determine the molecular structure of the racemates 1a-c and the absolute configuration of the enantiomers. The solid racemates 1b and 1c were "true racemates" crystallizing in a centrosymmetric space group, while 1a formed a racemic conglomerate of homoenantiomeric crystals. The absolute configuration was determined for the enantiomeric pairs (R)-10a/(S)-11a, (R)-10b/(S)-11b, and (R)-12c/(S)-13c, as well as for (3S,2S)-3a. Spectra of 1H, 13CNMR, HPLC, and HRMS for diastereomers and enantiomers were consistent with the determined structures.

5-HT Receptors and the Development of New Antidepressants.

Serotonin modulates several physiological and cognitive pathways throughout the human body that affect emotions, memory, sleep, and thermal regulation. The complex nature of the serotonergic system and interactions with other neurochemical systems indicate that the development of depression may be mediated by various pathomechanisms, the common denominator of which is undoubtedly the disturbed transmission in central 5-HT synapses. Therefore, the deliberate pharmacological modulation of serotonergic transmission in the brain seems to be one of the most appropriate strategies for the search for new antidepressants. As discussed in this review, the serotonergic system offers great potential for the development of new antidepressant therapies based on the combination of SERT inhibition with different pharmacological activity towards the 5-HT system. The aim of this article is to summarize the search for new antidepressants in recent years, focusing primarily on the possibility of benefiting from interactions with various 5-HT receptors in the pharmacotherapy of depression.

Synthesis of Novel Pyrido[1,2-c]pyrimidine Derivatives with 6-Fluoro-3-(4-piperidynyl)-1,2-benzisoxazole Moiety as Potential SSRI and 5-HT1A Receptor Ligands.

Two series of novel 4-aryl-2H-pyrido[1,2-c]pyrimidine (6a-i) and 4-aryl-5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine (7a-i) derivatives were synthesized. The chemical structures of the new compounds were confirmed by 1H and 13C NMR spectroscopy and ESI-HRMS spectrometry. The affinities of all compounds for the 5-HT1A receptor and serotonin transporter protein (SERT) were determined by in vitro radioligand binding assays. The test compounds demonstrated very high binding affinities for the 5-HT1A receptor of all derivatives in the series (6a-i and 7a-i) and generally low binding affinities for the SERT protein, with the exception of compounds 6a and 7g. Extended affinity tests for the receptors D2, 5-HT2A, 5-HT6 and 5-HT7 were conducted with regard to selected compounds (6a, 7g, 6d and 7i). All four compounds demonstrated very high affinities for the D2 and 5-HT2A receptors. Compounds 6a and 7g also had high affinities for 5-HT7, while 6d and 7i held moderate affinities for this receptor. Compounds 6a and 7g were also tested in vivo to identify their functional activity profiles with regard to the 5-HT1A receptor, with 6a demonstrating the activity profile of a presynaptic agonist. Metabolic stability tests were also conducted for 6a and 6d.

Understanding performance of 3D-printed sorbent in study of metabolic stability.

Metabolic stability tests are one of the fundamental steps at the preclinical stages of new drug development. Microsomes, used as a typical enzymatic model of liver biotransformation, can be a challenging matrix for analytical scientists due to a high concentration of cellular proteins and membrane lipids. In the work, we propose a new procedure integrating biotransformation reaction with SPME-like protocol for sample clean-up. It is beneficial to increase the overall quality of results in contrary to the typical protein precipitation approach. A set of ten arylpiperazine analogs, six of which are considered promising drug candidates (and four are accepted drugs) were used as a probe to assess the goodness of the newly proposed approach. In order to promote an efficient extraction protocol, a new, miniaturized shape of a sorbent, suitable to perform the extraction in 100 µL of the sample has been designed. Termination of the biotransformation process by protein denaturation with hot water was additionally evaluated. A quantitative structure-property relationship (QSPR) study using Orthogonal Partial Least Squares (OPLS) technique to reveal insights to the sorption mechanism was also performed. The obtained results showed the new 3D-printed sorbent can be an attractive basis for the new sample preparation approach for metabolic stability studies and an alternative for commercially available protocols based on solid-phase microextraction (SPME) or solid-phase extraction (SPE) principles.

Synthesis of new 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine derivatives with rigidized tryptamine moiety as potential SSRI and 5-HT1A receptor ligands.

Extended studies in the 4-aryl-pyrido[1,2-c]pyrimidine group resulted in 27 new compounds (10.1-10.27), 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine derivatives. In vitro tests (RBA) were carried out for 10.1-10.27 compounds in order to determine their affinity to 5-HT1A receptor and SERT protein. 10.1-10.3, 10.6, 10.7, 10.16 and 10.27 compounds had high binding ability to both molecular targets (5-HT1A Ki = 8-87 nM; SERT Ki = 8-52 nM). For these compounds (10.1-10.3, 10.6, 10.7, 10.16, 10.27) further in vitro, in vivo and metabolic stability tests were performed. In vitro studies in the extended receptor profile (D2, 5-HT2A, 5-HT6 and 5-HT7) showed their selectivity towards 5-HT1A receptor and SERT protein. In vivo tests revealed that compounds 10.7 and 10.16 had the properties of presynaptic antagonists of the 5-HT1A receptor. The redesign of the 2H-pyrido[1,2-c]pyrimidine residue present in the terminal part towards 5,6,7,8-tetrahydropyrido[1,2-c]pyrimidine resulted in the improved metabolic stability and enhanced affinity to both molecular targets (5-HT1A-R and SERT) compared to the precursors.

Synthesis of novel pyrido[1,2-c]pyrimidine derivatives with rigidized tryptamine moiety as potential SSRI and 5-HT1A receptor ligands.

The study enabled obtaining a number of new derivatives of 4-aryl-pyrido[1,2-c]pyrimidine 9.1-9.27 having conformationally restricted tryptamine moiety. In vitro studies (RBA) have shown that derivatives 9.1, 9.2, 9.4, 9.7, 9.9, 9.14 and 9.27 exhibit high affinity to molecular targets 5-HT1A receptor and SERT protein. In general, compounds with an unsubstituted or a para-substituted benzene ring of the pyrido[1,2-c]pyrimidine residue in the terminal part were characterized by higher binding ability, which can be justified by the greater flexibility of the structure. For the selected compounds 9.1, 9.7, 9.9 and 9.27, further in vitro, in vivo and metabolic stability tests were performed. The in vitro studies in the extended receptor profile (D2, 5-HT2A, 5-HT6 and 5-HT7) indicated their selectivity toward the 5-HT1A receptor and SERT protein. The in vivo studies (8-OH-DPAT-induced hypothermia in mice, FST) revealed that the compound 9.1 has the properties of presynaptic agonist of the 5-HT1A receptor, and compound 9.7 demonstrated the properties of a presynaptic antagonist of the 5-HT1A receptor. Metabolic stability studies, in turn, showed that compounds 9.1, 9.7 and 9.9, having an unsubstituted indole residue, were more resistant to biotransformation reactions of the first pass phase than was compound 9.27 containing a 5-methoxy-substituted indole residue. The obtained results allowed further optimization of the structure.

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

This work is a continuation of our previous research, concentrating this time on lead structure modification to increase the 5-HT1A receptor affinity and water solubility of designed compounds. Therefore, the compounds synthesised within the present project included structural analogues of 3ß-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 3ß-aminotropane derivatives was evaluated for their affinity for 5-HT1A, 5-HT2A, and D2 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.