TY - JOUR
T1 - Muscarinic cholinergic receptor binding
T2 - Influence of pimozide and chlorpromazine metabolites
AU - Yamamura, Henry I.
AU - Manian, Albert A.
AU - Snyder, Solomon H.
N1 - Funding Information:
Supported by Public Health Service grants MH-18501, DA-00266, MH-26967 and MH-27257, a Research Scientist Development Award MH-33128 to Solomon H . Snyder ; grants from the Committee to Combat Huntington's Disease, John A Hartford Foundation and Scottish Rite Foundation . Portions of this work was supported by a NIMH Special Research Fellowahip(MH-54777) and Research Scientist Development Award (MH-00095) to Henry I . Yamamura . Present address of H .I .Y ., Department of Pharmacology, Arizona Medical Center, Tucson, Arizona 85724 . We thank Peter Fagergren and James Clark for technical assistance . REFERENCES 1 . S .H . Stryder, D . Greenberg and 58-61 (1974) . 2 . R .J . Miller and C .R . Hiley, Nature Lond .) 248 . 596-597 (1974) . 3. P.A.J. Jansaea, J. Neuroaeschiat. 3 10-18 (1967) (Supp. 1) . 4. P.A.J. Jansaen and F.T.N. Allewijn, Arznelmittel-Forsch 18. 279-282 (1968) . 5 . P.A .J . Jansaea, W. Soudijn, I . vas Wijngaarden and A . Dresse, Arznel - mittel-Forsch 18 . 282-287 (1968) . 6. P.A. Morris D.$. Mackenzie and H.C. 683-684 (1970) . 7 . F .J . Ayd, International Drug Therapy Newsletter, V ,l No . 5 (1971) . 8 . S . Lal and T .L . Sourkes, Eur . J. Pharmacol . 17 . 283-286 X1972) . 9. G. Sakalis, T.L. Chap, S .Gershon and S . Park, PevchovharmacoloAia 32 . 279-284 (1973) .
PY - 1976/4/1
Y1 - 1976/4/1
N2 - The relative muscarinic anticholinergic actions of phenothiazines and related drugs are thought to regulate the propensity of these agents to elicit extrapyramidal side effects, especially those resembling the symptoms of Parkinson's disease. Pimozide, which closely resembles the butyrophenones in its chemical structure and its potent and selective dopamine receptor blockade, differs from the butyrophenones in its relatively low incidence of extrapyramidal side effects. In assays of the binding of 3H-quinuclidinyl benzilate (QNB) to muscarinic sites, pimozide displays a high affinity for these cholinergic receptors, similar to drugs, such as thioridizine and clozapine, which also have a low incidence of extrapyramidal side effects. This observation supports the notion that muscarinic anticholinergic actions can ameliorate the propensity of a drug to elicit extrapyramidal effects. The structure-activity relationships of chlorpromazine metabolites in binding to muscarinic sites in the brain parallels some of their structure-activity relationships as neuroleptic agents. 7-Hydroxychlorpromazine, which has been proposed as an antischizophrenic drug, binds to the muscarinic receptor with a potency similar to that of chlorpromazine itself, suggesting that the incidence of extrapyramidal side effects of 7-hydroxychlorpromazine might be similar to those of chlorpromazine.
AB - The relative muscarinic anticholinergic actions of phenothiazines and related drugs are thought to regulate the propensity of these agents to elicit extrapyramidal side effects, especially those resembling the symptoms of Parkinson's disease. Pimozide, which closely resembles the butyrophenones in its chemical structure and its potent and selective dopamine receptor blockade, differs from the butyrophenones in its relatively low incidence of extrapyramidal side effects. In assays of the binding of 3H-quinuclidinyl benzilate (QNB) to muscarinic sites, pimozide displays a high affinity for these cholinergic receptors, similar to drugs, such as thioridizine and clozapine, which also have a low incidence of extrapyramidal side effects. This observation supports the notion that muscarinic anticholinergic actions can ameliorate the propensity of a drug to elicit extrapyramidal effects. The structure-activity relationships of chlorpromazine metabolites in binding to muscarinic sites in the brain parallels some of their structure-activity relationships as neuroleptic agents. 7-Hydroxychlorpromazine, which has been proposed as an antischizophrenic drug, binds to the muscarinic receptor with a potency similar to that of chlorpromazine itself, suggesting that the incidence of extrapyramidal side effects of 7-hydroxychlorpromazine might be similar to those of chlorpromazine.
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U2 - 10.1016/0024-3205(76)90179-X
DO - 10.1016/0024-3205(76)90179-X
M3 - Article
C2 - 1263751
AN - SCOPUS:0017225937
SN - 0024-3205
VL - 18
SP - 685
EP - 691
JO - Life Sciences
JF - Life Sciences
IS - 7
ER -