TY - JOUR
T1 - 3H-haloperidol binding to dopamine receptors in rat corpus striatum
T2 - Influence of chlorpromazine metabolites and derivatives
AU - Creese, Ian
AU - Manian, Albert A.
AU - Prosser, Timothy D.
AU - Snyder, Solomon H.
N1 - Funding Information:
Susan M. Garonski is thanked for manuscript preparation. This research was supported by USPHS grant MH-18501 to S.H.S. and DA-05328 (USPHS Fellowship) to I.C.
Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 1978/2/1
Y1 - 1978/2/1
N2 - A series of chlorpromazine metabolites and derivatives have been assayed for their ability to compete with 3H-haloperidol binding to dopamine receptors in membranes of rat corpus striatum. 3-Hydroxylation of chlorpromazine doubles affinity for receptor sites, while 7-hydroxychlorpromazine has a potency similar to that of chlorpromazine itself. Other patterns of hydroxylation reduce affinity. Side chain demethylation lowers affinity for binding sites. Several metabolites which lack neuroleptic activity in vivo, such as chlorpromazine-5-oxide, also are inactive in competing for 3H-haloperidol binding. Since blood levels of 7-hydroxychlorpromazine tend to be similar to those of chlorpromazine itself in patients, these observations indicate that 7-hydroxychlorpromazine may account for a major portion of the antischizophrenic efficacy of chlorpromazine. The structure-activity relationship observed in the present study support a model in which chlorpromazine interacts with dopamine receptors by assuming a conformation with its side chain tilted toward ring A.
AB - A series of chlorpromazine metabolites and derivatives have been assayed for their ability to compete with 3H-haloperidol binding to dopamine receptors in membranes of rat corpus striatum. 3-Hydroxylation of chlorpromazine doubles affinity for receptor sites, while 7-hydroxychlorpromazine has a potency similar to that of chlorpromazine itself. Other patterns of hydroxylation reduce affinity. Side chain demethylation lowers affinity for binding sites. Several metabolites which lack neuroleptic activity in vivo, such as chlorpromazine-5-oxide, also are inactive in competing for 3H-haloperidol binding. Since blood levels of 7-hydroxychlorpromazine tend to be similar to those of chlorpromazine itself in patients, these observations indicate that 7-hydroxychlorpromazine may account for a major portion of the antischizophrenic efficacy of chlorpromazine. The structure-activity relationship observed in the present study support a model in which chlorpromazine interacts with dopamine receptors by assuming a conformation with its side chain tilted toward ring A.
KW - 7-Hydroxychlorpromazine
KW - Chlorpromazine
KW - Chlorpromazine metabolites and derivatives
KW - Dopamine receptors
KW - H-Haloperidol binding
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U2 - 10.1016/0014-2999(78)90236-4
DO - 10.1016/0014-2999(78)90236-4
M3 - Article
C2 - 631182
AN - SCOPUS:0017904404
SN - 0014-2999
VL - 47
SP - 291
EP - 296
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 3
ER -