In vitro pharmacological profile of YM-43611, a novel D2-like receptor antagonist with high affinity and selectivity for dopamine D3 and D4 receptors.
1. We investigated some neurochemical properties of a novel benzamide, YM-43611, [(S)-N-(1-benzyl-3-pyrrolidinyl)-5-chloro-4-cyclopropylcarbonylamino+ ++-2- methoxybenzamide] in comparison with putative D2-like receptor antagonists using both rat and human cloned dopamine D2-like receptors in vitro. 2. Receptor binding studies revealed that YM-43611 had appropriately potent affinities for both rat and human D2-like receptors, with moderate selectivity for D3 receptors and high selectivity for D4 receptors over D2 receptors (Ki values (nM) for rat receptors: D2, 165; D3, 35.5; D4, 1.85, and for human receptors: D2, 42.9; D3, 11.2; D4, 2.10). 3. YM-43611 displayed weak or negligible affinity for other neurotransmitter receptors, namely D1, D5, alpha(1), alpha(2), beta, 5-HT1A, 5-HT2A, 5-HT3, H1, M1 and M2 receptors. 4. Dopamine stimulated low-Km GTPase activity on membranes from Chinese hamster ovary (CHO) cells expressing the human D2-like receptor subtype. This response to dopamine of low-Km GTPase activity was inhibited by use of putative D2-like receptor antagonists. YM-43611 showed a moderate selectivity for D3 receptors (Ki = 45.5 nM) and a high selectivity for D4 receptors (Ki = 3.28 nM) over D2 receptors (Ki = 70.6 nM). 5. Dopamine inhibited forskolin-stimulated adenylate cyclase in intact CHO cells expressing the human D2-like receptor subtype. YM-43611 shifted the inhibition curve of dopamine on respective D2-like receptor subtype-mediated cyclic AMP formation to the right in a parallel fashion, showing a pA2 value of 7.42 (38.1 nM) for D2 receptors, a pKB value of 8.06 (8.68 nM) for D3 receptors, and a pA2 value of 8.42 (3.77 nM) for D4 receptors. 6. YM-43611 but not the other D2-like receptor antagonists exhibited good selectivity with respect to dual antagonism for D3 and D4 receptors in both receptor binding and functional assays. 7. These results indicate that YM-43611 is a novel D2-like receptor antagonist with high potency and selectivity for both D3 and D4 receptors. YM-43611 is therefore expected to be valuable in exploration of the physiological role of D3 and D4 receptors.
Hidaka
K
K
Neuroscience and Gastrointestinal Research Laboratory, Yamanouchi Pharmaceutical Co. Ltd., Ibaraki, Japan.
Tada
S
S
Matsumoto
M
M
Ohmori
J
J
Tasaki
Y
Y
Nomura
T
T
Usuda
S
S
Yamaguchi
T
T
D000818:Animals; D001483:Base Sequence; D001549:Benzamides / Q000378:metabolism* / Q000494:pharmacology; D001667:Binding, Competitive; D016466:CHO Cells / Q000737:chemistry / Q000378:metabolism; D006224:Cricetinae; D018492:Dopamine Antagonists / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism*; D050637:Receptors, Dopamine D3; D050638:Receptors, Dopamine D4
D001549:Benzamides; C493593:DRD3 protein, human; C493599:DRD4 protein, human; D018492:Dopamine Antagonists; C493595:Drd3 protein, rat; C493601:Drd4 protein, rat; C100801:N-(1-benzyl-3-pyrrolidinyl)-5-chloro-4-((cyclopropylcarbonyl)amino)-2-methoxybenzamide; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D050638:Receptors, Dopamine D4