Differential interactions of nateglinide and repaglinide on the human beta-cell sulphonylurea receptor 1.
Repaglinide and nateglinide represent a new class of insulin secretagogues, structurally unrelated to sulphonylureas, that were developed for the treatment of type 2 diabetes. The inhibitory effect of these drugs was investigated on recombinant wild-type and mutant Kir6.2/SUR1 channels expressed in...
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| Fformat: | Journal article |
| Iaith: | English |
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2002
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| _version_ | 1826291579267055616 |
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| author | Hansen, A Christensen, I Hansen, J Carr, R Ashcroft, F Wahl, P |
| author_facet | Hansen, A Christensen, I Hansen, J Carr, R Ashcroft, F Wahl, P |
| author_sort | Hansen, A |
| collection | OXFORD |
| description | Repaglinide and nateglinide represent a new class of insulin secretagogues, structurally unrelated to sulphonylureas, that were developed for the treatment of type 2 diabetes. The inhibitory effect of these drugs was investigated on recombinant wild-type and mutant Kir6.2/SUR1 channels expressed in HEK293 cells. Nateglinide and repaglinide dose-dependently inhibited whole-cell Kir6.2/SUR1 currents with half-maximal inhibitory concentration (IC(50)) values of 800 and 21 nmol/l, respectively. Mutation of serine 1237 in SUR1 to tyrosine (S1237Y) abolished tolbutamide and nateglinide block, suggesting that these drugs share a common point of interaction on the SUR1 subunit of the ATP-sensitive K(+) channel. In contrast, repaglinide inhibition was unaffected by the S1237Y mutation (IC(50) = 23 nmol/l). Radioligand binding studies revealed a single high-affinity binding site for [(3)H]repaglinide on membranes prepared from HEK293 cells expressing wild-type (equilibrium dissociation constant [K(D)] = 0.40 nmol/l) or mutant (K(D) = 0.31 nmol/l) Kir6.2/SUR1 channels. Nateglinide and tolbutamide displaced [(3)H]repaglinide binding to wild-type channels with IC(50) values of 0.7 and 26 micro mol/l, respectively, but produced <10% displacement of [(3)H]repaglinide bound to mutant channels. This is consistent with the idea that binding of nateglinide and tolbutamide, but not repaglinide, is abolished by the SUR1[S1237Y] mutation and that the binding site for repaglinide is not identical to that of nateglinde/tolbutamide. These results are discussed in terms of a conformational analysis of the drug molecules. |
| first_indexed | 2024-03-07T03:01:31Z |
| format | Journal article |
| id | oxford-uuid:b11e5c61-e6ab-47dd-aca3-e23a4a36441c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T03:01:31Z |
| publishDate | 2002 |
| record_format | dspace |
| spelling | oxford-uuid:b11e5c61-e6ab-47dd-aca3-e23a4a36441c2022-03-27T04:01:36ZDifferential interactions of nateglinide and repaglinide on the human beta-cell sulphonylurea receptor 1.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:b11e5c61-e6ab-47dd-aca3-e23a4a36441cEnglishSymplectic Elements at Oxford2002Hansen, AChristensen, IHansen, JCarr, RAshcroft, FWahl, PRepaglinide and nateglinide represent a new class of insulin secretagogues, structurally unrelated to sulphonylureas, that were developed for the treatment of type 2 diabetes. The inhibitory effect of these drugs was investigated on recombinant wild-type and mutant Kir6.2/SUR1 channels expressed in HEK293 cells. Nateglinide and repaglinide dose-dependently inhibited whole-cell Kir6.2/SUR1 currents with half-maximal inhibitory concentration (IC(50)) values of 800 and 21 nmol/l, respectively. Mutation of serine 1237 in SUR1 to tyrosine (S1237Y) abolished tolbutamide and nateglinide block, suggesting that these drugs share a common point of interaction on the SUR1 subunit of the ATP-sensitive K(+) channel. In contrast, repaglinide inhibition was unaffected by the S1237Y mutation (IC(50) = 23 nmol/l). Radioligand binding studies revealed a single high-affinity binding site for [(3)H]repaglinide on membranes prepared from HEK293 cells expressing wild-type (equilibrium dissociation constant [K(D)] = 0.40 nmol/l) or mutant (K(D) = 0.31 nmol/l) Kir6.2/SUR1 channels. Nateglinide and tolbutamide displaced [(3)H]repaglinide binding to wild-type channels with IC(50) values of 0.7 and 26 micro mol/l, respectively, but produced <10% displacement of [(3)H]repaglinide bound to mutant channels. This is consistent with the idea that binding of nateglinide and tolbutamide, but not repaglinide, is abolished by the SUR1[S1237Y] mutation and that the binding site for repaglinide is not identical to that of nateglinde/tolbutamide. These results are discussed in terms of a conformational analysis of the drug molecules. |
| spellingShingle | Hansen, A Christensen, I Hansen, J Carr, R Ashcroft, F Wahl, P Differential interactions of nateglinide and repaglinide on the human beta-cell sulphonylurea receptor 1. |
| title | Differential interactions of nateglinide and repaglinide on the human beta-cell sulphonylurea receptor 1. |
| title_full | Differential interactions of nateglinide and repaglinide on the human beta-cell sulphonylurea receptor 1. |
| title_fullStr | Differential interactions of nateglinide and repaglinide on the human beta-cell sulphonylurea receptor 1. |
| title_full_unstemmed | Differential interactions of nateglinide and repaglinide on the human beta-cell sulphonylurea receptor 1. |
| title_short | Differential interactions of nateglinide and repaglinide on the human beta-cell sulphonylurea receptor 1. |
| title_sort | differential interactions of nateglinide and repaglinide on the human beta cell sulphonylurea receptor 1 |
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