Identification of a butyrophenone analog as a potential atypical antipsychotic agent: 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one.
The synthesis and exploration of novel butyrophenones have led to the identification of a diazepane analogue of haloperidol, 4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one (compound 13) with an interesting multireceptor binding profile. Compound 13 was evaluated for its binding affinities at DA subtype receptors, 5HT subtype receptors, H-1, M-1 receptors and at NET, DAT, and SERT transporters. At each of these receptors, compound 13 was equipotent or better than several of the standards currently in use. In in vivo mouse and rat models to evaluate its efficacy and propensity to elicit catalepsy and hence EPS in humans, compound 13 showed similar efficacy as clozapine and did not produce catalepsy at five times its ED(50) value.
Ablordeppey
Seth Y
SY
Division of Basic Pharmaceutical Sciences, Florida A&M University, College of Pharmacy and Pharmaceutical Sciences, Tallahassee, FL 32307, USA. seth.ablordeppey@famu.edu
Altundas
Ramazan
R
Bricker
Barbara
B
Zhu
Xue Y
XY
Kumar
Eyunni V K Suresh
EV
Jackson
Tanise
T
Khan
Abdul
A
Roth
Bryan L
BL
D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001058:Apomorphine / Q000494:pharmacology; D001381:Azepines / Q000737:chemistry* / Q000494:pharmacology*; D002090:Butyrophenones / Q000737:chemistry* / Q000494:pharmacology*; D003024:Clozapine / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013239:Stereotyped Behavior / Q000187:drug effects; D013329:Structure-Activity Relationship
C532761:4-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-1-(4-fluuorophenyl)butan-1-one; D014150:Antipsychotic Agents; D001381:Azepines; D002090:Butyrophenones; D003024:Clozapine; D006220:Haloperidol; D001058:Apomorphine