Pharmacological actions of a novel, high-affinity, and selective human dopamine D(3) receptor antagonist, SB-277011-A.
SB-277011-A (trans-N-[4-[2-(6-cyano-1,2,3, 4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolininecarboxamide), is a brain-penetrant, high-affinity, and selective dopamine D(3) receptor antagonist. Radioligand-binding experiments in Chinese hamster ovary (CHO) cells transfected with human dopamine D(3) or D(2 long) (hD(3), hD(2)) receptors showed SB-277011-A to have high affinity for the hD(3) receptor (pK(i) = 7.95) with 100-fold selectivity over the hD(2) receptor and over 66 other receptors, enzymes, and ion channels. Similar radioligand-binding data for SB-277011-A were obtained from CHO cells transfected with rat dopamine D(3) or D(2). In the microphysiometer functional assay, SB-277011-A antagonized quinpirole-induced increases in acidification in CHO cells overexpressing the hD(3) receptor (pK(b) = 8.3) and was 80-fold selective over hD(2) receptors. Central nervous system penetration studies showed that SB-277011-A readily entered the brain. In in vivo microdialysis studies, SB-277011-A (2. 8 mg/kg p.o.) reversed the quinelorane-induced reduction of dopamine efflux in the nucleus accumbens but not striatum, a regional selectivity consistent with the distribution of the dopamine D(3) receptor in rat brain. SB-277011-A (2-42.3 mg/kg p.o.) did not affect spontaneous locomotion, or stimulant-induced hyperlocomotion. SB-277011-A (4.1-42.2 mg/kg p.o.) did not reverse prepulse inhibition deficits in apomorphine- or quinpirole-treated rats, but did significantly reverse the prepulse inhibition deficit in isolation-reared rats at a dose of 3 mg/kg p.o. SB-277011-A (2.5-78. 8 mg/kg p.o.) was noncataleptogenic and did not raise plasma prolactin levels. Thus, dopamine D(3) receptor blockade produces few of the behavioral effects characteristic of nonselective dopamine receptor antagonists. The effect of SB-277011-A on isolation-induced prepulse inhibition deficit suggests that blockade of dopamine D(3) receptors may benefit the treatment of schizophrenia.
Reavill
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Department of Neuroscience Research, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, Essex, United Kingdom. Charlie_Reavill-1@SBPHRD-.COM
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D000818:Animals; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D002375:Catalepsy / Q000139:chemically induced; D006224:Cricetinae; D018492:Dopamine Antagonists / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009570:Nitriles / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D011388:Prolactin / Q000097:blood; D011804:Quinolines / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D011869:Radioligand Assay; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D050637:Receptors, Dopamine D3; D013216:Reflex, Startle / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044005:Tetrahydroisoquinolines; D014162:Transfection
C493593:DRD3 protein, human; D018492:Dopamine Antagonists; C493595:Drd3 protein, rat; D009570:Nitriles; D011804:Quinolines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C409982:SB 277011; D044005:Tetrahydroisoquinolines; D011388:Prolactin