Radaieva I. The “structure-neurotropic activity” relationship in the new 3-substituted derivatives of 1,4-benzodiazepine

This thesis considers the “structure-neurotropic activity” of the new 3-substituted derivatives of 1,4-benzodiazepine. The analysis of the “structure-activity” in the line of esters and ethers 7-brom-5-(2'-chlor)phenyl-1,2-dihydro-3Н-1,4-benzodiazepine-2-one and 7-brom-5-phenyl-1,2-dihydro-3Н-1,4-benzodiazepine-2-one has shown that there are two basic structural components which have a large effect on the pharmacological activity of 3-substituted derivatives of 1,4-benzodiazepine. One of those is the administration of substitutes into the heterocyclic ring’s third position thus decreasing the anticonvulsant activity which in case of esters gradually recovers by virtue of a released active metabolite, or, in case of ethers, slowly decreases over time. On the other side, a Cl atom in the ortho-oriented phenyl fragment causes more decreased anticonvulsant activity, and in case of ethers 7-brom-5-(2'-chlor)phenyl-1,2-dihydro-3Н-1,4-benzodiazepine-2-one this leads to almost completely lost anticonvulsant activity after 24 hours of the oral administration. The most active compounds required some pharmacological tests (black-and-white camera, open field and rotating rod), so as to examine the neurotropic activity. The research of the distribution pattern of esters 7-brom-5-(2'-chlor)phenyl-1,2-dihydro-3Н-1,4-benzodiazepine-2-one in organs and tissues of experimental animals in vivo has shown that most of the esters and 3-hydroxyphenazepam after oral administration are found within the brain.