AFFINITY OF NEW POTENTIAL LIGANDS OF THE GABAA-RECEPTOR COMPLEX AND TSPO RECEPTORS OF THE CNS – cis-3-ARYLIDENE-7-BROMO-5-ARYL-1,2-DIHYDRO-3H-1,4-BENZODIAZEPIN-2-ONES

1,4-Benzodiazepines are chemical compounds with various neurotropic properties. Previously, we synthesized a series of 3-arylidene-1,2-dihydro-3H-1,4-benzodiazepin-2-ones and showed that some these compounds exhibit pronounced affinity for GABAA receptors and TSPO receptors of the CNS. In this regard, we synthesized a series of new 3-arylidene-1,2-dihydro-3H-1,4-benzodiazepin-2-ones 3–11 for the purpose of further studying the affinity for GABAA receptors and TSPO receptors of the CNS. The aim of this work was to study the affinity of 3-arylidene-7-bromo-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepin-2-ones 3–11 for GABAA receptors and TSPO receptors, the synthesis and a number of pharmacological properties of which we have previously described. Compounds 3–11 were synthesized under Knoevenagel condensation conditions as a result of the reaction of 1,4-benzodiazepin-2-ones 1–2 with the corresponding aromatic aldehydes by boiling the components in toluene in the presence of catalytic amounts of dry potassium carbonate. The affinity of the synthesized compounds for the GABAA and TSPO receptors of the central nervous system was studied. The affinity of compounds 3–11 was determined in vitro by radioligand analysis based on their ability to displace commercial radioligands [3H]flumazenil and [3H]PK11195 from their specific binding sites in the GABAA receptor complex and TSPO receptor complex of synaptic and mitochondrial fractions of rat brain membranes, respectively. It has been shown that the introduction of a chlorine atom into the ortho position of the 5-phenyl radical of the 7-bromo-5-phenyl-3-(2’-chloroarylidene)-1,2-dihydro-3H-1,4-benzodiazepin-2-one molecule (4) leads to the production of a compound (7) with a higher affinity for GABAAR. It was established that the compounds 6 and 9, which contain a para-chloroarylidene substituent in the third position of the diazepine ring, have the highest affinity for GABA receptors and have inhibition values (I,%) of 78.2±7.6% and 74.5±8.0%, respectively. For compound 9, the affinity for the GABA receptor was determined, Ki = 245.5 nM. It should be noted that the introduction of a chlorine atom into the ortho-position of the 5-phenyl radical of the 3-arylidene-1,4-benzodiazepin-2-one molecule affects the affinity for TSPO receptors, as evidenced by an increase in the % inhibition of specific binding of the radioligand [3H]PK 11195 for TSPO receptors. It was established that in the series of 5-phenyl- and 5-ortho-chlorophenyl-3-arylidene-7-bromo-1,2-dihydro-3H-1,4-benzodiazepin-2-ones studied, the following patterns of influence of the position of the chlorine atom in the arylidene fragment on the affinity for GABAAR and TSPO receptors can be traced:mеtа – Cl >> ortho – Cl > pаrа – Cl (affinity for GABAAR) Summarizing the results of our long-term research, it was established that the main structural fragment that determines the binding tropism of 3-arylidene-1,4-benzodiazepin-2-ones with TSPO receptors is the presence of an electronegative substituent in the para-position of the benzylidene fragment:pаrа – Hal>> ortho – Hal> mеta – Hal (affinity for TSPO),(Hal = Br, F, Cl)Thus, the expediency of further study of this class of compounds is shown.