Article date: May 2003
By: Domenico Tricarico, Mariagrazia Barbieri, Laghezza Antonio, Paolo Tortorella, Fulvio Loiodice, Diana Conte Camerino in Volume 139, Issue 2, pages 255-262
New 2H‐1,4‐benzoxazine derivatives were synthesized and tested for their agonist properties on the ATP‐sensitive K+ channels (KATP) of native rat skeletal muscle fibres by using the patch‐clamp technique. The novel modifications involved the introduction at position 2 of the benzoxazine ring of alkyl substituents such as methyl (–CH3), ethyl (–C2H5) or propyl (–C3H7) groups, while maintaining pharmacophore groups critical for conferring agonist properties.
The effects of these molecules were compared with those of cromakalim in the presence or absence of internal ATP (10−4M). In the presence of internal ATP, all the compounds increased the macropatch KATP currents. The order of potency of the molecules as agonists was −C3H7 (DE50=1.63 × 10−8M) >−C2H5 (DE50=1.11 × 10−7M)>–CH3 (DE50=2.81 × 10−7M)>cromak‐slim (DE50= 1.42 × 10−5M). Bell‐shaped dose–response curves were observed for these compounds and cromakalim indicating a downturn in response when a certain dose was exceeded.
In contrast, in the absence of internal ATP, all molecules including cromakalim inhibited the KATP currents. The order of increasing potency as antagonists was cromakalim (IC50=1.15 × 10−8M)–CH3 (IC50=2.6 × 10−8M)>–C2H5 (IC50=4.4 × 10−8M)>–C3H7 (IC50=1.68 × 10−7M) derivatives.
These results suggest that the newly synthesized molecules and cromakalim act on muscle KATP channel by binding on two receptor sites that have opposite actions. Alternatively, a more simple explanation is to consider the existence of a single site for potassium channel openers regulated by ATP which favours the transduction of the channel opening. The alkyl chains at position 2 of the 2H‐1,4‐benzoxazine nucleus is pivotal in determining the potency of benzoxazine derivatives as agonists or antagonists.
New 2H‐1,4‐benzoxazine derivatives were synthesized and tested for their agonist properties on the ATP‐sensitive K+ channels (KATP) of native rat skeletal muscle fibres by using the patch‐clamp technique. The novel modifications involved the introduction at position 2 of the benzoxazine ring of alkyl substituents such as methyl (–CH3), ethyl (–C2H5) or propyl (–C3H7) groups, while maintaining pharmacophore groups critical for conferring agonist properties.
The effects of these molecules were compared with those of cromakalim in the presence or absence of internal ATP (10−4M). In the presence of internal ATP, all the compounds increased the macropatch KATP currents. The order of potency of the molecules as agonists was −C3H7 (DE50=1.63 × 10−8M) >−C2H5 (DE50=1.11 × 10−7M)>–CH3 (DE50=2.81 × 10−7M)>cromak‐slim (DE50= 1.42 × 10−5M). Bell‐shaped dose–response curves were observed for these compounds and cromakalim indicating a downturn in response when a certain dose was exceeded.
In contrast, in the absence of internal ATP, all molecules including cromakalim inhibited the KATP currents. The order of increasing potency as antagonists was cromakalim (IC50=1.15 × 10−8M)–CH3 (IC50=2.6 × 10−8M)>–C2H5 (IC50=4.4 × 10−8M)>–C3H7 (IC50=1.68 × 10−7M) derivatives.
These results suggest that the newly synthesized molecules and cromakalim act on muscle KATP channel by binding on two receptor sites that have opposite actions. Alternatively, a more simple explanation is to consider the existence of a single site for potassium channel openers regulated by ATP which favours the transduction of the channel opening. The alkyl chains at position 2 of the 2H‐1,4‐benzoxazine nucleus is pivotal in determining the potency of benzoxazine derivatives as agonists or antagonists.
British Journal of Pharmacology (2003) 139, 255–262. doi:10.1038/sj.bjp.0705233
DOI: 10.1038/sj.bjp.0705233
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