Interaction of AZA analogs of chlorpromazine with the dopamine D2 receptor.
1. Permanently charged AZA analogs of chlorpromazine inhibited the binding of [3H]spiperone and antagonized the apomorphine-induced inhibition of the potassium evoked release of [3H]acetylcholine. 2. The AZA analogs were more potent in binding affinity and antagonist activity than the trimethylammonium analog of chlorpromazine but less potent than chlorpromazine. 3. These results suggest that it is possible to enhance the binding of the permanently charged trimethylammonium analog of chlorpromazine by the addition of a functional group near the quaternary nitrogen which is capable of forming a hydrogen bond with the D2 dopamine receptor. 4. However, it appears that for optimal binding, as achieved with chlorpromazine, the hydrogen-bonding proton should be on the charged nitrogen.
Farooqui
T
T
Division of Pharmacology and Medicinal Chemistry, College of Pharmacy, Ohio State University, Columbus 43210.
Markovich
K
K
Wallace
L
L
Miller
D
D
Uretsky
N
N
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001372:Aza Compounds / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D002746:Chlorpromazine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D011188:Potassium / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D013134:Spiperone / Q000378:metabolism
D001372:Aza Compounds; D000644:Quaternary Ammonium Compounds; D017448:Receptors, Dopamine D2; D013134:Spiperone; D001058:Apomorphine; D000109:Acetylcholine; D011188:Potassium; D002746:Chlorpromazine