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In vitro pharmacological profile of YM‐43611, a novel D 2 ‐like receptor antagonist with high affinity and selectivity for dopamine D 3 and D 4 receptors
Author(s) -
Hidaka Kazuyuki,
Tada Shoko,
Matsumoto Mitsuyuki,
Ohmori Junya,
Tasaki Yoshikazu,
Nomura Tamako,
Usuda Shinji,
Yamaguchi Tokio
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15332.x
Subject(s) - receptor , chinese hamster ovary cell , metabotropic receptor , dopamine receptor , chemistry , dopamine , agonist , biology , medicine , endocrinology , biochemistry
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 D 2 ‐like receptor antagonists using both rat and human cloned dopamine D 2 ‐like receptors in vitro . 2 Receptor binding studies revealed that YM‐43611 had appropriately potent affinities for both rat and human D 2 ‐like receptors, with moderate selectivity for D 3 receptors and high selectivity for D 4 receptors over D 2 receptors (Kt values (nM) for rat receptors: D 2 , 165; D 3 , 35.5; D 4 , 1.85, and for human receptors: D 2 42.9; D 3 , 11.2; D 4 , 2.10). 3 YM‐43611 displayed weak or negligible affinity for other neurotransmitter receptors, namely D 1 , D 5 , α 1 , α 2 , β, 5‐HT 1A , 5‐HT 2A , 5‐HT 3 , H 1 , M 1 and M 2 receptors. 4 Dopamine stimulated low‐K m GTPase activity on membranes from Chinese hamster ovary (CHO) cells expressing the human D 2 ‐like receptor subtype. This response to dopamine of low‐K m GTPase activity was inhibited by use of putative D 2 ‐like receptor antagonists. YM‐43611 showed a moderate selectivity for D 3 receptors ( Ki =45.5 nM) and a high selectivity for D 4 receptors ( K i =3.28 nM) over D 2 receptors ( K i =70.6 nM). 5 Dopamine inhibited forskolin‐stimulated adenylate cyclase in intact CHO cells expressing the human D 2 ‐like receptor subtype. YM‐43611 shifted the inhibition curve of dopamine on respective D 2 ‐like receptor subtype‐mediated cyclic AMP formation to the right in a parallel fashion, showing a pA 2 value of 7.42 (38.1 nM) for D 2 receptors, a p K B > value of 8.06 (8.68 nM) for D 3 receptors, and a p A 2 value of 8.42 (3.77 nM) for D 4 receptors. 6 YM‐43611 but not the other D 2 ‐like receptor antagonists exhibited good selectivity with respect to dual antagonism for D 3 and D 4 receptors in both receptor binding and functional assays. 7 These results indicate that YM‐43611 is a novel D 2 ‐like receptor antagonist with high potency and selectivity for both D 3 and D 4 receptors. YM‐43611 is therefore expected to be valuable in exploration of the physiological role of D 3 and D 4 receptors.