Pyrroloisoquinoline antidepressants. 3. A focus on serotonin.
A collection of hexahydropyrroloisoquinoline derivatives (1-22), which represent a class of compounds that inhibit the neuronal uptake of dopamine (DA), norepinephrine (NE), and serotonin (5-HT), was investigated in vivo for serotonin-potentiating properties in the mouse head-twitch and rat serotonin syndrome assays. The p-methylthio compound 3b (McN-5652-Z) was found to possess exceptional activity in these assays, and the activity was attributable almost exclusively to the (+)-6S,10bR enantiomer. Ten closely related analogues were synthesized, tested, and compared among themselves and with some previously prepared compounds, both in vivo and in vitro. Several trans diastereomers exhibited strong inhibition of 5-HT uptake and substantial potentiation of 5-HT, while the cis diastereomers (3a, 4a, and 10a) tested were virtually devoid of such activity. Although 3b was only moderately selective in inhibiting the uptake of 5-HT vs NE, its 10-substituted analogues 4b, 7b-9b had improved 5-HT selectivity relative to NE, to the extent of 20-25 times (150-200 times relative to DA). Of these more selective compounds (in vitro), only 4b and 7b had substantial activity in vivo. Sulfoxide 11b appeared to function as a prodrug of 3b in vivo.
Maryanoff
B E
BE
Department of Chemical Research, McNeil Pharmaceutical, Spring House, Pennsylvania 19477.
Vaught
J L
JL
Shank
R P
RP
McComsey
D F
DF
Costanzo
M J
MJ
Nortey
S O
SO
D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis*; D001681:Biological Assay; D001692:Biological Transport / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D012701:Serotonin / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000928:Antidepressive Agents; D007546:Isoquinolines; D011758:Pyrroles; D012701:Serotonin