Low-basicity 5-HT7 receptor agonists synthesized using the van Leusen multicomponent protocol

A series of 5-aryl-1-alkylimidazole derivatives was synthesized using the van Leusen multicomponent reaction. The chemotype is the first example of low-basicity scaffolds exhibiting high affinity for 5-HT7 receptor together with agonist function. The chosen lead compounds 3-(1-ethyl-1H-imidazol-5-yl)-5- iodo-1H-indole (AGH-107, 1o, Ki 5-HT7=6nM, EC50=19nM, 176-fold selectivity over 5-HT1AR) and 1e (5-methoxy analogue, Ki 5-HT7=30nM, EC50=60nM) exhibited high selectivity over related CNS targets, high metabolic stability and low toxicity in HEK-293 and HepG2 cell cultures. A rapid absorption to the blood, high blood-brain barrier permeation and a very high peak concentration in the brain (Cmax=2723 ng/g) were found for 1o after i.p. (5mg/kg) administration in mice. The compound was found active in novel object recognition test in mice, at 0.5, 1 and 5mg/kg. Docking to 5-HT7R homology models indicated a plausible binding mode which explain the unusually high selectivity over the related CNS targets. Halogen bond formation between the most potent derivatives and the receptor is consistent with both the docking results and SAR. 5-Chlorine, bromine and iodine substitution resulted in a 13, 27 and 89-fold increase in binding affinities, respectively, and in enhanced 5-HT1AR selectivity

Design and synthesis of new quinazolin-4-one derivatives with negative mGlu7mGlu_7 receptor modulation activity and antipsychotic-like properties

Following the glutamatergic theory of schizophrenia and based on our previous study regarding the antipsychotic-like activity of mGlu7 NAMs, we synthesized a new compound library containing 103 members, which were examined for NAM mGlu7 activity in the T-REx 293 cell line expressing a recombinant human mGlu7 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(3H)-one (A9-7, ALX-171, mGlu7 IC50 = 6.14 µM) was selective over other group III mGlu receptors (mGlu4 and mGlu8), 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

Distinct cognitive and discriminative stimulus effects of ketamine enantiomers in rats

Although (S)-ketamine was approved for use in treatment-resistant depression in 2019, new preclinical findings suggest that (R)-ketamine might produce better efficacy and tolerability relative to (S)-ketamine. Here we evaluated the effects of (R)-, (S)-, and (R,S)-ketamine on executive functions as measured in the attentional set shifting task (ASST) and on their discriminative stimulus effects in rats. Earlier data demonstrated that cognitive flexibility is compromised by (R,S)-ketamine, but the effects of enantiomers in rats are unknown. Separate cohorts of rats were tested in ASST and trained to discriminate either (R,S)-ketamine, (S)-ketamine, or (R)-ketamine (all at 10 mg/kg) from saline; in order to maintain the discrimination, a higher (R)-ketamine dose (17.5 mg/kg) was subsequently instituted. In ASST, all three forms increased the trials to criterion measure at reversal learning and extra-dimensional set-shifting phases. However, in contrast to (R)- and (S)-ketamine, (R,S)-ketamine prolonged the mean time to complete a single trial during early stages, suggesting increased reaction time, and/or unspecific side-effects related to motor or motivational impairments. In the drug discriminations, all rats acquired their respective discriminations between drug and saline. In (R,S)-ketamine-trained rats, (R)-ketamine and (S)-ketamine only partially substituted for the training dose of (R,S)-ketamine. Further, (R)-ketamine did not fully substitute in rats trained to (S)-ketamine. The data suggest more serious cognitive deficits produced by (R,S)-ketamine than its enantiomers. Furthermore, (R,S)-ketamine and its isomers share overlapping but not isomorphic discriminative stimulus effects predicting distinct subjective responses to (R)- vs. (S)-ketamine in humans

Design and synthesis of anticancer Mdm2-p53 complex antagonists

Obecnie, prowadzonych jest wiele badań dotyczących nowoczesnych terapii przeciwnowotworowych, z czego najwięcej dotyczy interakcji białek Mdm2-p53. Białko p53 reguluje w komórce wiele ważnych procesów, takich jak: naprawa DNA, autofagocytoza, starzenie komórki, apoptoza. Rolą Mdm2 jest m.in. regulacja poziomu p53. W wielu komórkach nowotworowych występuje mutacja genu kodującego p53 lub wadliwe mechanizmy regulowania ilości p53, czego przykładem jest nadekspresja Mdm2. Na chwilę obecną, w I fazie badań klinicznych znajduje się 6 związków, wykazujących wysokie powinowactwo do białka Mdm2, z których największe szanse na szerokie zastosowanie medyczne ma Nutlin-3.Celem niniejszej pracy magisterskiej było zaprojektowanie oraz synteza nieznanych związków chemicznych opartych o szkielet pirolo-2-onu, potencjalnie wykazujących działanie antagonistyczne w stosunku do kompleksu białek Mdm2-p53. Opracowano dwa szlaki syntetyczne prowadzące do otrzymania dwóch par izomerów. Finalnie, udało się zsyntetyzować dwa izomery. Powinowactwo do białka Mdm2 otrzymanych produktów zmierzono, korzystając z dwuwymiarowych metod Jądrowego Rezonansu Magnetycznego (HSQC). Wyznaczona wartość stałej dysocjacji pozwoliła zaliczyć pierwszy izomer do grupy średniej mocy antagonistów. Drugi izomer nie wykazywał powinowactwa do białka Mdm2.Within numerous current cancer therapy researches, major emphasis is put on Mdm2-p53 interaction. p53 protein plays crucial role in cell life, controlling multiplex processes: DNA repair, autophagocytosis, cell aging, apoptosis. Mdm2 is an essential negative regulator of p53. p53 mutation or defective p53 mechanisms of regulation such as Mdm2 overexpression is observed in most cancer cells. There are six compounds in phase I clinical trials possesing high Mdm2 binding affinity, of which Nutlin-3 shows best therapeutic perspectives.The aim of hereinafter described research was the design, synthesis and evaluation of new chemical entities based on pyrol-2-one scaffold, potentially acting as Mdm2-p53 antagonists. Two distinctive synthetic routes for two pairs of isomeric organic molecules were proposed. Only one pair of isomers was obtained. Mdm2-ligand dissociation constants of the two synthesized compounds were measured via 2D nuclear magnetic resonance techniques (HSQC). Determined value of constants allow to include first isomer to group of medium binders, second isomer did not exhibit measurable affinity for Mdm2

N-skatyltryptamines - dual 5-HT6R/D2R ligands with antipsychotic and procognitive potential

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