Pyrrole mannich bases as potential antipsychotic agents.
Recently, we reported on a series of arylpiperazines 4 which exhibit high affinity for the serotonin 5-HT-1A and 5-HT-1B binding sites. Although these compounds interact weakly with dopamine D-1 and D-2 receptors, they are reasonably potent in inhibiting conditioned avoidance responding (CAR) in the rat, an indication of potential antipsychotic activity. Conversion of these arylpiperazines to pyrrole Mannich bases has provided a series of compounds (10-44) which exhibit potent inhibition of CAR when given po and have strong affinity for both the D-2 and 5-HT-1A binding sites. Some of these agents also fail to produce catalepsy. The D-2 binding data and the block of CAR suggest that they are potential antipsychotic agents and the lack of cataleptogenic potential suggests some might possess less liability for producing extrapyramidal side effects and tardive dyskinesias in man.
Department of Biological Research, McNeil Pharmaceutical, R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477.
M K
MK
Scott
G E
GE
Martin
D L
DL
DiStefano
C L
CL
Fedde
M J
MJ
Kukla
D L
DL
Barrett
W J
WJ
Baldy
R J
RJ
Elgin
J M
JM
Kesslick
J R
JR
Mathiasen
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects; D008297:Male; D008352:Mannich Bases / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D014150:Antipsychotic Agents; D008352:Mannich Bases; D011954:Receptors, Dopamine; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin