Potential antidepressant activity and enhancement of serotonin uptake of a new dibenzothiadiazepine derivative.
A molecule, 6-methyl-6,11-dihydro-11-[(N,N-dimethylamino) acetyl]dibenzo[c,fl-[1,2,5]thiadiazepine 5,5-dioxide, (IM/P/3/4, CAS 128377-70-8), was identified in a screening program, which had the scope of finding compounds with antidepressive potential without the common sideeffects of existing antidepressive medication. IM/P/3/4 was found active a) in antagonizing apomorphine (16 mg/kg) and reserpine-induced hypothermia in mice; b) in potentiating yohimbine-induced lethality in mice; c) in reducing immobility of rats forced to swim and of mice suspended by the tail. IM/P/3/4 does not affect a) apomorphine-induced stereotypy; b) amphetamine-induced hypermotility; c) haloperidol-induced catalepsy and water-induced grooming and d) does not induce stereotypy or alter motor activity. The compound also a) reduced the beating of rat right heart atria only at a concentration of 3 x 10-4 mol/l; b) had weak anticholinergic activity; c) antagonized electroshock-induced convulsions and d) prevented indometacin-induced duodenal ulcers. IM/P/3/4 does not have good affinity for noradrenergic, serotonergic, dopaminergic, histaminergic or muscarinic receptors and does not displace imipramine, desipramine and mianserine from their binding sites. IM/P/3/4 increases 5-hydroxyindolacetic acid content and 3H-serotonin uptake in the hypothalamus. The present results suggest that IM/P/3/4 is a potential antidepressant with reduced side effects and with a mechanism of action which is different from that of other antidepressants.
Borsini
F
F
Menarini Pharmaceuticals, Research Department, Firenze, Italy.
Volterra
G
G
Lecci
A
A
Evangelista
S
S
Mancinelli
A
A
Cutrufo
C
C
Parlani
M
M
Mennini
T
T
Barone
D
D
Meli
A
A
D000777:Anesthetics / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D000928:Antidepressive Agents / Q000494:pharmacology*; D014150:Antipsychotic Agents; D001058:Apomorphine / Q000494:pharmacology; D015306:Biogenic Monoamines / Q000378:metabolism; D001831:Body Temperature / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D003292:Convulsants / Q000494:pharmacology; D003913:Dextroamphetamine / Q000494:pharmacology; D004064:Digestive System / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010276:Parasympatholytics / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012110:Reserpine / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism*; D013841:Thiazepines / Q000494:pharmacology*; D015016:Yohimbine / Q000633:toxicity
D000777:Anesthetics; D000927:Anticonvulsants; D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D015306:Biogenic Monoamines; D003292:Convulsants; D010276:Parasympatholytics; D013841:Thiazepines; C071160:6-methyl-6,11-dihydro-11-((N,N-dimethylamino)acetyl)dibenzo(c,f)-(1,2,5)-thiadiazepine 5,5-dioxide; D015016:Yohimbine; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D012110:Reserpine; D001058:Apomorphine; D003913:Dextroamphetamine