Structure-affinity profile of 8-hydroxycarbostyril-based agonists that dissociate slowly from the β2-adrenoceptor
Deyrup, M. D. ; Nowicki, S. T. ; Richards, N. G. J. ; Otero, D. H. ; Harrison, J. K. ; Baker, S. P.
Springer
Published 1999
Springer
Published 1999
| ISSN: |
1432-1912
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|---|---|
| Keywords: |
Key words β-Adrenoceptor receptor ; Insurmountable ; agonist ; Structure activity ; cAMP ; Carbostyril β-agonist
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| Source: |
Springer Online Journal Archives 1860-2000
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| Topics: |
Medicine
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| Notes: |
Abstract Several carbostyril-based β-agonists have been shown to bind tightly to and slowly dissociate from the β2-adrenoceptor (β2AR). In the present study, the structural features of 8-hydroxy-5-[2-[(1-phenyl-2-methylprop-2-yl)amino]-1-hydroxyethyl]-carbostyril (11a) which contribute to its binding properties at the β2AR were investigated using a series of synthesized analogs. The k off, estimated by the rate of cAMP decline in DDT1 MF-2 (DDT) cells with a reduced receptor density, K i and ligand-induced receptor reductions were determined. All of the derivatives stimulated cAMP accumulation in DDT cells in the sub to mid nanomolar range and elicited the same maximal stimulation as (–)isoproterenol. Derivatives of 11a with side chain N-substitutions comprising 2-methylbutyl, phenyl-ethyl and isopropyl had higher k off-values and lower affinities as compared to 11a. Increasing the number of methylenes between the side chain tertiary alpha carbon and phenyl from 1 in 11a to 3 or reducing the number to 0 also resulted in derivatives with higher k off- and K i-values. In addition, replacement of the 8-hydroxycarbostyril nucleus of 11a with catechol reduced the affinity of the compound for the β2AR by 48-fold and increased its k off. Only those derivatives with the lowest k off-values induced a decrease in the receptor density of DDT cell membranes following a preincubation and extensive washing. The data show that the 8-hydroxycarbostyril nucleus in conjunction with substitutions on the tertiary alpha carbon of the side chain and positioning of the phenyl group are important characteristics determining the high affinity and slow dissociation of 11a from the β2AR.
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| Type of Medium: |
Electronic Resource
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| URL: |
| _version_ | 1798295847504445440 |
|---|---|
| autor | Deyrup, M. D. Nowicki, S. T. Richards, N. G. J. Otero, D. H. Harrison, J. K. Baker, S. P. |
| autorsonst | Deyrup, M. D. Nowicki, S. T. Richards, N. G. J. Otero, D. H. Harrison, J. K. Baker, S. P. |
| book_url | http://dx.doi.org/10.1007/PL00005339 |
| datenlieferant | nat_lic_papers |
| hauptsatz | hsatz_simple |
| identnr | NLM200650033 |
| issn | 1432-1912 |
| journal_name | Naunyn-Schmiedeberg's archives of pharmacology |
| materialart | 1 |
| notes | Abstract Several carbostyril-based β-agonists have been shown to bind tightly to and slowly dissociate from the β2-adrenoceptor (β2AR). In the present study, the structural features of 8-hydroxy-5-[2-[(1-phenyl-2-methylprop-2-yl)amino]-1-hydroxyethyl]-carbostyril (11a) which contribute to its binding properties at the β2AR were investigated using a series of synthesized analogs. The k off, estimated by the rate of cAMP decline in DDT1 MF-2 (DDT) cells with a reduced receptor density, K i and ligand-induced receptor reductions were determined. All of the derivatives stimulated cAMP accumulation in DDT cells in the sub to mid nanomolar range and elicited the same maximal stimulation as (–)isoproterenol. Derivatives of 11a with side chain N-substitutions comprising 2-methylbutyl, phenyl-ethyl and isopropyl had higher k off-values and lower affinities as compared to 11a. Increasing the number of methylenes between the side chain tertiary alpha carbon and phenyl from 1 in 11a to 3 or reducing the number to 0 also resulted in derivatives with higher k off- and K i-values. In addition, replacement of the 8-hydroxycarbostyril nucleus of 11a with catechol reduced the affinity of the compound for the β2AR by 48-fold and increased its k off. Only those derivatives with the lowest k off-values induced a decrease in the receptor density of DDT cell membranes following a preincubation and extensive washing. The data show that the 8-hydroxycarbostyril nucleus in conjunction with substitutions on the tertiary alpha carbon of the side chain and positioning of the phenyl group are important characteristics determining the high affinity and slow dissociation of 11a from the β2AR. |
| package_name | Springer |
| publikationsjahr_anzeige | 1999 |
| publikationsjahr_facette | 1999 |
| publikationsjahr_intervall | 8004:1995-1999 |
| publikationsjahr_sort | 1999 |
| publisher | Springer |
| reference | 359 (1999), S. 168-177 |
| schlagwort | Key words β-Adrenoceptor receptor Insurmountable agonist Structure activity cAMP Carbostyril β-agonist |
| search_space | articles |
| shingle_author_1 | Deyrup, M. D. Nowicki, S. T. Richards, N. G. J. Otero, D. H. Harrison, J. K. Baker, S. P. |
| shingle_author_2 | Deyrup, M. D. Nowicki, S. T. Richards, N. G. J. Otero, D. H. Harrison, J. K. Baker, S. P. |
| shingle_author_3 | Deyrup, M. D. Nowicki, S. T. Richards, N. G. J. Otero, D. H. Harrison, J. K. Baker, S. P. |
| shingle_author_4 | Deyrup, M. D. Nowicki, S. T. Richards, N. G. J. Otero, D. H. Harrison, J. K. Baker, S. P. |
| shingle_catch_all_1 | Deyrup, M. D. Nowicki, S. T. Richards, N. G. J. Otero, D. H. Harrison, J. K. Baker, S. P. Structure-affinity profile of 8-hydroxycarbostyril-based agonists that dissociate slowly from the β2-adrenoceptor Key words β-Adrenoceptor receptor Insurmountable agonist Structure activity cAMP Carbostyril β-agonist Key words β-Adrenoceptor receptor Insurmountable agonist Structure activity cAMP Carbostyril β-agonist Abstract Several carbostyril-based β-agonists have been shown to bind tightly to and slowly dissociate from the β2-adrenoceptor (β2AR). In the present study, the structural features of 8-hydroxy-5-[2-[(1-phenyl-2-methylprop-2-yl)amino]-1-hydroxyethyl]-carbostyril (11a) which contribute to its binding properties at the β2AR were investigated using a series of synthesized analogs. The k off, estimated by the rate of cAMP decline in DDT1 MF-2 (DDT) cells with a reduced receptor density, K i and ligand-induced receptor reductions were determined. All of the derivatives stimulated cAMP accumulation in DDT cells in the sub to mid nanomolar range and elicited the same maximal stimulation as (–)isoproterenol. Derivatives of 11a with side chain N-substitutions comprising 2-methylbutyl, phenyl-ethyl and isopropyl had higher k off-values and lower affinities as compared to 11a. Increasing the number of methylenes between the side chain tertiary alpha carbon and phenyl from 1 in 11a to 3 or reducing the number to 0 also resulted in derivatives with higher k off- and K i-values. In addition, replacement of the 8-hydroxycarbostyril nucleus of 11a with catechol reduced the affinity of the compound for the β2AR by 48-fold and increased its k off. Only those derivatives with the lowest k off-values induced a decrease in the receptor density of DDT cell membranes following a preincubation and extensive washing. The data show that the 8-hydroxycarbostyril nucleus in conjunction with substitutions on the tertiary alpha carbon of the side chain and positioning of the phenyl group are important characteristics determining the high affinity and slow dissociation of 11a from the β2AR. 1432-1912 14321912 Springer |
| shingle_catch_all_2 | Deyrup, M. D. Nowicki, S. T. Richards, N. G. J. Otero, D. H. Harrison, J. K. Baker, S. P. Structure-affinity profile of 8-hydroxycarbostyril-based agonists that dissociate slowly from the β2-adrenoceptor Key words β-Adrenoceptor receptor Insurmountable agonist Structure activity cAMP Carbostyril β-agonist Key words β-Adrenoceptor receptor Insurmountable agonist Structure activity cAMP Carbostyril β-agonist Abstract Several carbostyril-based β-agonists have been shown to bind tightly to and slowly dissociate from the β2-adrenoceptor (β2AR). In the present study, the structural features of 8-hydroxy-5-[2-[(1-phenyl-2-methylprop-2-yl)amino]-1-hydroxyethyl]-carbostyril (11a) which contribute to its binding properties at the β2AR were investigated using a series of synthesized analogs. The k off, estimated by the rate of cAMP decline in DDT1 MF-2 (DDT) cells with a reduced receptor density, K i and ligand-induced receptor reductions were determined. All of the derivatives stimulated cAMP accumulation in DDT cells in the sub to mid nanomolar range and elicited the same maximal stimulation as (–)isoproterenol. Derivatives of 11a with side chain N-substitutions comprising 2-methylbutyl, phenyl-ethyl and isopropyl had higher k off-values and lower affinities as compared to 11a. Increasing the number of methylenes between the side chain tertiary alpha carbon and phenyl from 1 in 11a to 3 or reducing the number to 0 also resulted in derivatives with higher k off- and K i-values. In addition, replacement of the 8-hydroxycarbostyril nucleus of 11a with catechol reduced the affinity of the compound for the β2AR by 48-fold and increased its k off. Only those derivatives with the lowest k off-values induced a decrease in the receptor density of DDT cell membranes following a preincubation and extensive washing. The data show that the 8-hydroxycarbostyril nucleus in conjunction with substitutions on the tertiary alpha carbon of the side chain and positioning of the phenyl group are important characteristics determining the high affinity and slow dissociation of 11a from the β2AR. 1432-1912 14321912 Springer |
| shingle_catch_all_3 | Deyrup, M. D. Nowicki, S. T. Richards, N. G. J. Otero, D. H. Harrison, J. K. Baker, S. P. Structure-affinity profile of 8-hydroxycarbostyril-based agonists that dissociate slowly from the β2-adrenoceptor Key words β-Adrenoceptor receptor Insurmountable agonist Structure activity cAMP Carbostyril β-agonist Key words β-Adrenoceptor receptor Insurmountable agonist Structure activity cAMP Carbostyril β-agonist Abstract Several carbostyril-based β-agonists have been shown to bind tightly to and slowly dissociate from the β2-adrenoceptor (β2AR). In the present study, the structural features of 8-hydroxy-5-[2-[(1-phenyl-2-methylprop-2-yl)amino]-1-hydroxyethyl]-carbostyril (11a) which contribute to its binding properties at the β2AR were investigated using a series of synthesized analogs. The k off, estimated by the rate of cAMP decline in DDT1 MF-2 (DDT) cells with a reduced receptor density, K i and ligand-induced receptor reductions were determined. All of the derivatives stimulated cAMP accumulation in DDT cells in the sub to mid nanomolar range and elicited the same maximal stimulation as (–)isoproterenol. Derivatives of 11a with side chain N-substitutions comprising 2-methylbutyl, phenyl-ethyl and isopropyl had higher k off-values and lower affinities as compared to 11a. Increasing the number of methylenes between the side chain tertiary alpha carbon and phenyl from 1 in 11a to 3 or reducing the number to 0 also resulted in derivatives with higher k off- and K i-values. In addition, replacement of the 8-hydroxycarbostyril nucleus of 11a with catechol reduced the affinity of the compound for the β2AR by 48-fold and increased its k off. Only those derivatives with the lowest k off-values induced a decrease in the receptor density of DDT cell membranes following a preincubation and extensive washing. The data show that the 8-hydroxycarbostyril nucleus in conjunction with substitutions on the tertiary alpha carbon of the side chain and positioning of the phenyl group are important characteristics determining the high affinity and slow dissociation of 11a from the β2AR. 1432-1912 14321912 Springer |
| shingle_catch_all_4 | Deyrup, M. D. Nowicki, S. T. Richards, N. G. J. Otero, D. H. Harrison, J. K. Baker, S. P. Structure-affinity profile of 8-hydroxycarbostyril-based agonists that dissociate slowly from the β2-adrenoceptor Key words β-Adrenoceptor receptor Insurmountable agonist Structure activity cAMP Carbostyril β-agonist Key words β-Adrenoceptor receptor Insurmountable agonist Structure activity cAMP Carbostyril β-agonist Abstract Several carbostyril-based β-agonists have been shown to bind tightly to and slowly dissociate from the β2-adrenoceptor (β2AR). In the present study, the structural features of 8-hydroxy-5-[2-[(1-phenyl-2-methylprop-2-yl)amino]-1-hydroxyethyl]-carbostyril (11a) which contribute to its binding properties at the β2AR were investigated using a series of synthesized analogs. The k off, estimated by the rate of cAMP decline in DDT1 MF-2 (DDT) cells with a reduced receptor density, K i and ligand-induced receptor reductions were determined. All of the derivatives stimulated cAMP accumulation in DDT cells in the sub to mid nanomolar range and elicited the same maximal stimulation as (–)isoproterenol. Derivatives of 11a with side chain N-substitutions comprising 2-methylbutyl, phenyl-ethyl and isopropyl had higher k off-values and lower affinities as compared to 11a. Increasing the number of methylenes between the side chain tertiary alpha carbon and phenyl from 1 in 11a to 3 or reducing the number to 0 also resulted in derivatives with higher k off- and K i-values. In addition, replacement of the 8-hydroxycarbostyril nucleus of 11a with catechol reduced the affinity of the compound for the β2AR by 48-fold and increased its k off. Only those derivatives with the lowest k off-values induced a decrease in the receptor density of DDT cell membranes following a preincubation and extensive washing. The data show that the 8-hydroxycarbostyril nucleus in conjunction with substitutions on the tertiary alpha carbon of the side chain and positioning of the phenyl group are important characteristics determining the high affinity and slow dissociation of 11a from the β2AR. 1432-1912 14321912 Springer |
| shingle_title_1 | Structure-affinity profile of 8-hydroxycarbostyril-based agonists that dissociate slowly from the β2-adrenoceptor |
| shingle_title_2 | Structure-affinity profile of 8-hydroxycarbostyril-based agonists that dissociate slowly from the β2-adrenoceptor |
| shingle_title_3 | Structure-affinity profile of 8-hydroxycarbostyril-based agonists that dissociate slowly from the β2-adrenoceptor |
| shingle_title_4 | Structure-affinity profile of 8-hydroxycarbostyril-based agonists that dissociate slowly from the β2-adrenoceptor |
| sigel_instance_filter | dkfz geomar wilbert ipn albert fhp |
| source_archive | Springer Online Journal Archives 1860-2000 |
| timestamp | 2024-05-06T09:42:39.953Z |
| titel | Structure-affinity profile of 8-hydroxycarbostyril-based agonists that dissociate slowly from the β2-adrenoceptor |
| titel_suche | Structure-affinity profile of 8-hydroxycarbostyril-based agonists that dissociate slowly from the β2-adrenoceptor |
| topic | WW-YZ |
| uid | nat_lic_papers_NLM200650033 |