Junya Ohmori

YM-50001 : a novel, potent and selective dopamine D4 receptor antagonist

We investigated some in vitro pharmacological properties of a novel human dopamine D2-like receptor antagonist, YM-50001 [(R)-5-chloro-4-cyclopropylacarbonylamino-2-methoxy-N-[1-(3-methox ybenzyl)- 3-pyrrolidinyl]benzamide monooxalate]. Receptor binding studies revealed that YM-50001 had a potent affinity for human D4 receptors (Ki = 5.62 nM). YM-50001 displayed weak or negligible affinity for other neurotransmitter receptors including human D2 and D3 receptors. YM-50001 shifted the dopamine response curve on each human D2-like receptor subtype-mediated low-Km GTPase activity to the right. YM-50001 also exhibited good D4 selectivity with respect to D2-like receptor antagonism in the functional assay. These results indicate that YM-50001 is a novel, potent and selective D4 receptor antagonist.

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)‐S‐(1‐benzyl‐3‐pyrrolidinyl)‐5‐chloro‐4‐cyclopropylcarbonyl‐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 (Ktvalues (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, α1, α2, β, 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.