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The serotonin 5-HT 6 receptor (5-HT 6 R), expressed almost exclusively in the brain, affects the Cdk5 signaling as well as the mTOR pathway. Due to the association of 5-HT 6 R signaling with pathways involved in cancer progression, we decided to check the usefulness of 5-HT 6 R ligands in the treatment of CNS tumors. For this purpose, a new group of low-base 5-HT 6 R ligands was developed, belonging to arylsulfonamide derivatives of cyclic arylguanidines. The selected group of molecules was also tested for their antiproliferative activity on astrocytoma (1321N1) and glioblastoma (U87MG, LN-229, U-251) cell lines. Some of the molecules were subjected to ADMET tests in vitro, including lipophilicity, drug binding to plasma proteins, affinity for phospholipids, drug-drug interaction (DDI), the penetration of the membrane (PAMPA), metabolic stability, and hepatotoxicity as well as in vivo cardiotoxicity in the Danio rerio model. Two antagonists with an affinity constant K i < 50 nM ( PR 68 K i = 37 nM) were selected. These compounds were characterized by very high selectivity. An analysis of pharmacokinetic parameters for the lead compound PR 68 confirmed favorable properties for administration, including passive diffusion and acceptable metabolic stability (metabolized in 49%, MLMs). The compound did not exhibit the potential for drug-drug interactions.

Following the glutamatergic theory of schizophrenia and based on our previous study regarding the antipsychotic-like activity of mGlu 7 NAMs, we synthesized a new compound library containing 103 members, which were examined for NAM mGlu 7 activity in the T-REx 293 cell line expressing a recombinant human mGlu 7 receptor. Out of the twenty-two scaffolds examined, active compounds were found only within the quinazolinone chemotype. 2-(2-Chlorophenyl)-6-(2,3-dimethoxyphenyl)-3-methylquinazolin-4(3 H )-one ( A9-7 , ALX-171 , mGlu 7 IC 50 = 6.14 µM) was selective over other group III mGlu receptors (mGlu 4 and mGlu 8 ), exhibited satisfactory drug-like properties in preliminary DMPK profiling, and was further tested in animal models of antipsychotic-like activity, assessing the positive, negative, and cognitive symptoms. ALX-171 reversed DOI-induced head twitches and MK-801-induced disruptions of social interactions or cognition in the novel object recognition test and spatial delayed alternation test. On the other hand, the efficacy of the compound was not observed in the MK-801-induced hyperactivity test or prepulse inhibition. In summary, the observed antipsychotic activity profile of ALX-171 justifies the further development of the group of quinazolin-4-one derivatives in the search for a new drug candidate for schizophrenia treatment.

A series of N -skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT 1A , 5-HT 2A , 5-HT 6 , and D 2 receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D 2 receptor antagonists with additional 5-HT 6 R antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HT 6 R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT 6 R agonists was more ambiguous-in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds 15 and 18 , we tried to sort out the difference between ligands exhibiting the D 2 R antagonist function combined with 5-HT 6 R agonism, and mixed D 2 /5-HT 6 R antagonists in murine models of psychosis.

The complex pathophysiology of depression, together with the limits of currently available antidepressants, has resulted in the continuous quest for alternative therapeutic strategies. Numerous findings suggest that pharmacological blockade of α 2 -adrenoceptor might be beneficial for the treatment of depressive symptoms by increasing both norepinephrine and serotonin levels in certain brain areas. Moreover, the antidepressant properties of 5-HT 7 receptor antagonists have been widely demonstrated in a large set of animal models. Considering the potential therapeutic advantages in targeting both α 2 -adrenoceptors and 5-HT 7 receptors, we designed a small series of arylsulfonamide derivatives of (dihydrobenzofuranoxy)ethyl piperidines as dually active ligands. Following green chemistry principles, the designed compounds were synthesized entirely using a sustainable mechanochemical approach. The identified compound 8 behaved as a potent α 2A /5-HT 7 receptor antagonist and displayed moderate-to-high selectivity over α 1 -adrenoceptor subtypes and selected serotonin and dopaminergic receptors. Finally, compound 8 improved performance of mice in the forced swim test, displaying similar potency to the reference drug mirtazapine.

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 1 H and 13 C NMR spectroscopy and ESI-HRMS spectrometry. The affinities of all compounds for the 5-HT 1A 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-HT 1A 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 D 2 , 5-HT 2A , 5-HT 6 and 5-HT 7 were conducted with regard to selected compounds ( 6a , 7g , 6d and 7i ). All four compounds demonstrated very high affinities for the D 2 and 5-HT 2A receptors. Compounds 6a and 7g also had high affinities for 5-HT 7 , 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-HT 1A receptor, with 6a demonstrating the activity profile of a presynaptic agonist. Metabolic stability tests were also conducted for 6a and 6d .

Two sets of new o-methoxyphenylpiperazine (MPP; series a) and 1,2,3,4-tetrahydroisoquinoline (THIQ; series b) derivatives, containing various imide moieties derived from NAN190, were synthesized and evaluated in vitro for their ability to bind to the serotonin 5-HT(1A) and 5-HT(2A) receptors. All new derivatives from series a demonstrated high 5-HT(1A) affinities, whereas THIQ analogues were much less active. With respect to 5-HT(2A) receptors, three MPP derivatives presented moderate activity but the rest of the investigated compounds were practically inactive. The influence of changes in terminus geometry on 5-HT(1A) receptor affinity was analyzed in regard to model compounds NAN190and MM199.