Synthesis and pharmacological testing of 1,2,3,4,10,14b-hexahydro-6-methoxy-2-methyldibenzo[c,f]pyrazino[1,2-a]azepin and its enantiomers in comparison with the two antidepressants mianserin and mirtazapine.
The synthesis and resolution of 1,2,3,4,10,14b-hexahydro-6-methoxy-2-methyldibenzo[c,f]pyrazino[1,2-a]azepin (6-methoxymianserin, 6) are described. Furthermore, the in vitro and in vivo effects of 6 and its enantiomers are presented. 6 displayed high affinity for the 5-HT2A/2C receptors, only moderate affinity for the adrenoceptors, and no affinity for the NA reuptake site. Surprisingly, 6 also showed moderate to high affinity for the dopamine D2 receptor, an effect that resides in the (R)-(-)-enantiomer.
Department of Medicinal Chemistry, University Center for Pharmacy, University of Groningen, A. Deusinglaan 1, NL-9713 AV, Groningen, The Netherlands. h.v.wikstrom@farm.rug.nl
Håkan V
HV
Wikström
Marguérite M
MM
Mensonides-Harsema
Thomas I F H
TI
Cremers
Ejner K
EK
Moltzen
Jørn
J
Arnt
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008803:Mianserin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017551:Microdialysis; D000078785:Mirtazapine; D009638:Norepinephrine / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011941:Receptors, Adrenergic / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C461657:6-methoxymianserin; D000928:Antidepressive Agents; D011941:Receptors, Adrenergic; D011954:Receptors, Dopamine; D011968:Receptors, Histamine; D011985:Receptors, Serotonin; D015102:3,4-Dihydroxyphenylacetic Acid; D008803:Mianserin; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D000078785:Mirtazapine; D009638:Norepinephrine