title: Pyrrolobenzodiazepines and related systems. 2. Synthesis and biological properties of isonoraptazepine derivatives.
abstract: 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 alpha 2 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.
authors.affiliation: Dipartimento di Studi Farmaceutici, Università di Roma La Sapienza, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Massa
authors.forename: M
authors.initials: M
authors.lastname: Artico
authors.forename: A
authors.initials: A
authors.lastname: Mai
authors.forename: F
authors.initials: F
authors.lastname: Corelli
authors.forename: M
authors.initials: M
authors.lastname: Botta
authors.forename: A
authors.initials: A
authors.lastname: Tafi
authors.forename: G C
authors.initials: GC
authors.lastname: Pantaleoni
authors.forename: R
authors.initials: R
authors.lastname: Giorgi
authors.forename: M F
authors.initials: MF
authors.lastname: Coppolino
authors.forename: A
authors.initials: A
authors.lastname: Cagnotto
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D005260:Female; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D000928:Antidepressive Agents; D011942:Receptors, Adrenergic, alpha; C078817:isonoraptazepine; D001569:Benzodiazepines; D012701:Serotonin; D007099:Imipramine