Biochemical and pharmacological evaluation of the novel antidepressant and serotonin uptake inhibitor 2-(3,4-Dichlorobenzyl)-2-dimethylamino-1-propanol hydrochloride.
2-(3,4-Dichlorobenzyl)-2-dimethylamino-1-propanol, hydrochloride (JO 1017) is a novel antidepressant drug. Its biochemical and pharmacological properties were investigated in mice, rats, dogs, rabbits and guinea pigs. In vitro, it selectively inhibited serotonin uptake and had a high affinity for the 3H-paroxetine and 3H-imipramine binding sites. Biochemical studies demonstrated the lack of MAO-A and MAO-B inhibition and the absence of marked affinity for muscarinic, histaminic or other conventional brain receptors. Chronic treatment with JO 1017 induced a decrease in the Bmax values for imipramine sites but did not modify the Bmax for beta-adrenergic and 5-HT2 receptors. The neuropsychopharmacological profile of JO 1017 is characterized by a decrease of the immobility times in behavioural despair tests with mice, a decrease of the escape failures in the rat learned helplessness test, a strong potentiation of L-5-HT P-induced head-twitches in mice and an antagonism of reserpine-induced ptosis in rabbits. It weakly antagonized oxotremorine-induced hypothermia and did not influence the hypothermia induced by apomorphine. In contrast to most other antidepressants, a high dose of JO 1017 induced hypermotility in mice placed in an activity meter without producing stereotyped behaviour and group toxicity. Unlike tricyclic antidepressants, JO 1017 was devoid of severe cardiotoxicity in guinea pigs and had no central anticholinergic nor antihistaminic properties. These results suggest that JO 1017 is a selective serotonin uptake inhibitor with a high safety margin. JO 1017 may have a potential clinical utility both in the treatment of depression and for indications where serotonin transmission is involved, e.g., anxiety, panic attack, obsessive compulsive disorder, obesity and alcohol consumption.
Gouret
C J
CJ
Institut de Recherche Jouveinal, Fresnes, France.
Porsolt
R
R
Wettstein
J G
JG
Puech
A
A
Soulard
C
C
Pascaud
X
X
Junien
J L
JL
D000818:Animals; D000927:Anticonvulsants; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001665:Binding Sites / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002395:Catecholamines / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D006168:Guinea Pigs; D006331:Heart Diseases / Q000139:chemically induced / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D007099:Imipramine / Q000378:metabolism; D008297:Male; D051379:Mice; D008996:Monoamine Oxidase Inhibitors; D011412:Propanolamines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*
D000927:Anticonvulsants; D000928:Antidepressive Agents; D002395:Catecholamines; D008996:Monoamine Oxidase Inhibitors; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D007099:Imipramine; C065524:cericlamine