3-aminopyridazine derivatives with atypical antidepressant, serotonergic, and dopaminergic activities.
Minaprine [3-[(beta-morpholinoethyl)amino]-4-methyl-6-phenylpyridazine dihydrochloride] is active in most animal models of depression and exhibits in vivo a dual dopaminomimetic and serotoninomimetic activity profile. In an attempt to dissociate these two effects and to characterize the responsible structural requirements, a series of 47 diversely substituted analogues of minaprine were synthesized and tested for their potential antidepressant, serotonergic, and dopaminergic activities. The structure-activity relationships show that dopaminergic and serotonergic activities can be dissociated. Serotonergic activity appears to be correlated mainly with the substituent in the 4-position of the pyridazine ring whereas the dopaminergic activity appears to be dependent on the presence, or in the formation, of a para-hydroxylated aryl ring in the 6-position of the pyridazine ring.
Wermuth
C G
CG
Departement de Pharmacochimie Moléculaire, Centre de Neurochimie du CNRS, Université Louis Pasteur, Strasbourg, France.
Schlewer
G
G
Bourguignon
J J
JJ
Maghioros
G
G
Bouchet
M J
MJ
Moire
C
C
Kan
J P
JP
Worms
P
P
Biziere
K
K
D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002621:Chemistry; D015259:Dopamine Agents / Q000138:chemical synthesis*; D005260:Female; D051379:Mice; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D011954:Receptors, Dopamine / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000928:Antidepressive Agents; D015259:Dopamine Agents; D011724:Pyridazines; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; C006149:minaprine