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In vitro pharmacological profile of YM-43611, a novel D2-like receptor antagonist with high affinity and selectivity for dopamine D3 and D4 receptors
| Content Provider | Scilit |
|---|---|
| Author | Hidaka, Kazuyuki Tada, Shoko Matsumoto, Mitsuyuki Ohmori, Junya Tasaki, Yoshikazu Nomura, Tamako Usuda, Shinji Yamaguchi, Tokio |
| Copyright Year | 1996 |
| Description | Journal: British Journal of Pharmacology |
| Abstract | 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 (Ktvalues (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 $pK_{B}$> value of 8.06 (8.68 nM) for $D_{3}$ receptors, and a $pA_{2}$ 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. |
| Ending Page | 1632 |
| Starting Page | 1625 |
| ISSN | 2573508X |
| e-ISSN | 14765381 |
| DOI | 10.1111/j.1476-5381.1996.tb15332.x |
| Journal | British Journal of Pharmacology |
| Issue Number | 8 |
| Volume Number | 117 |
| Language | English |
| Publisher | Wiley-Blackwell |
| Publisher Date | 1996-04-01 |
| Access Restriction | Open |
| Subject Keyword | Journal: British Journal of Pharmacology Medicinal Chemistry D2-like Receptors D3 Dopamine Receptor D4 Dopamine Receptor Adenylate Cyclase |
| Content Type | Text |
| Resource Type | Article |
