TY - JOUR
T1 - Pyrrolobenzodiazepines and related systems. 2. Synthesis and biological properties of isonoraptazepine derivatives
AU - Massa, S.
AU - Artico, M.
AU - Mai, A.
AU - Corelli, F.
AU - Botta, M.
AU - Tafi, A.
AU - Pantaleoni, G. C.
AU - Giorgi, R.
AU - Coppolino, M. F.
AU - Cagnotto, A.
AU - Skorupska, M.
PY - 1992
Y1 - 1992
N2 - The synthesis of some derivatives and analogues of 12,13,14,14a- tetrahydro-9H,11H-pyrazino-[2,1-c]pyrrolo[1,2-a][1,4]benzodiazepine (isonoraptazepine) is reported. The new derivatives have been subjected to pharmacological tests for evaluation of antidepressant effects. Neurobehavioral assays were also carried out to acquire data on neurotoxicity and sedative action. Isonoraptazepine analogues and derivatives lacked the pharmacological activity of mianserin and aptazepine and showed properties similar to imipramine. Molecular modeling studies revealed structural similarities between isonoraptazepine derivatives and imipramine, thus explaining the similar pharmacological profile found in some of the tests employed. Based on pharmacological data the title compounds cannot be regarded as α2 presynaptic adrenoceptors antagonists. In vitro studies for receptor binding gave support to this observation. The above studies lead us to conclude that isonoraptazepine derivatives are conformationally restricted analogues of imipramine, but their antidepressant activity cannot be correlated to inhibition of 5HT uptake. Among the derivatives tested, 7b and 8e show some affinity for the d-fenfluramine receptor site, a serotonin presynaptic site connected with anorectic activity.
AB - The synthesis of some derivatives and analogues of 12,13,14,14a- tetrahydro-9H,11H-pyrazino-[2,1-c]pyrrolo[1,2-a][1,4]benzodiazepine (isonoraptazepine) is reported. The new derivatives have been subjected to pharmacological tests for evaluation of antidepressant effects. Neurobehavioral assays were also carried out to acquire data on neurotoxicity and sedative action. Isonoraptazepine analogues and derivatives lacked the pharmacological activity of mianserin and aptazepine and showed properties similar to imipramine. Molecular modeling studies revealed structural similarities between isonoraptazepine derivatives and imipramine, thus explaining the similar pharmacological profile found in some of the tests employed. Based on pharmacological data the title compounds cannot be regarded as α2 presynaptic adrenoceptors antagonists. In vitro studies for receptor binding gave support to this observation. The above studies lead us to conclude that isonoraptazepine derivatives are conformationally restricted analogues of imipramine, but their antidepressant activity cannot be correlated to inhibition of 5HT uptake. Among the derivatives tested, 7b and 8e show some affinity for the d-fenfluramine receptor site, a serotonin presynaptic site connected with anorectic activity.
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U2 - 10.1021/jm00102a004
DO - 10.1021/jm00102a004
M3 - Article
C2 - 1335075
AN - SCOPUS:0027052394
VL - 35
SP - 4533
EP - 4541
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 24
ER -