Design and Synthesis of New Quinazolin-4-one Derivatives with Negative mGlu 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 mGlu NAMs, we synthesized a new compound library containing 103 members, which were examined for NAM mGlu activity in the T-REx 293 cell line expressing a recombinant human mGlu 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)-one (, , mGlu IC = 6.

New 1,2,4-oxadiazole derivatives with positive mGlu receptor modulation activity and antipsychotic-like properties.

Considering the allosteric regulation of mGlu receptors for potential therapeutic applications, we developed a group of 1,2,4-oxadiazole derivatives that displayed mGlu receptor positive allosteric modulatory activity (EC = 282-656 nM). Selectivity screening revealed that they were devoid of activity at mGlu, mGlu and mGlu receptors, but modulated mGlu and mGlu receptors, thus were classified as group III-preferring mGlu receptor agents. None of the compounds was active towards hERG channels or in the mini-AMES test.

New imide 5-HT1A receptor ligands - modification of terminal fragment geometry.

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.

Novel 4-alkyl-1-arylpiperazines and 1,2,3,4-tetrahydroisoquinolines containing diphenylmethylamino or diphenylmethoxy fragment with differentiated 5-HT1A/5-HT2A/D2 receptor activity.

Two series of 4-alkyl-1-arylpiperazines (1-4) and 1,2,3,4-tetrahydroiso-quinolines (5, 6) with diphenylmethylamino (series a) or diphenylmethoxy (series b) fragment were synthesized in order to obtain potential ligands of 5-HT1A and/or 5-HT2A and dopamine D2 receptors. Four new arylpiperazines (1a, 3a, 1b, 3b) were found to demonstrate high 5-HT1A receptor affinity (Ki = 1.5-35 nM); among them, 3a exhibited satisfactory 5-HT2A receptor affinity (Ki = 74 nM).

The influence of substitution at aromatic part of 1,2,3,4-tetrahydroisoquinoline on in vitro and in vivo 5-HT(1A)/5-HT(2A) receptor activities of its 1-adamantoyloaminoalkyl derivatives.

Further structure-activity relationship (SAR) studies with the 1,2,3,4-tetrahydroisoquinoline (THIQ) class of 5-HT(1A) ligands led to the synthesis of new 1-adamantoyloaminoalkyl derivatives. The impact of substituent variations in the aromatic part of THIQ moiety on 5-HT(1A) and 5-HT(2A) receptor affinities, as well as in vivo functional properties of the investigated compounds were discussed. It was found that those modifications reduced the binding affinity for 5-HT(1A) receptors (in comparison with unsubstituted THIQ derivatives); however, the majority of new compounds still remained potent 5-HT(1A) ligands (K(i)=4.