Pharmacological study of atypical β-adrenoceptors in rat esophageal smooth muscle

Edwin J. Lezama, Anish A. Konkar, M. Margarita Salazar-Bookaman, Duane Miller, Dennis R. Feller

Research output: Contribution to journalArticle

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Abstract

The chemical specificity for the β-adrenoceptor mediated relaxation of rat esophageal smooth muscle was evaluated using selective and non-selective β-adrenoceptor agonists and antagonists. Pindolol, ICI 89,406, ICI 11855 [erythro-1-(7-methylindan-4-yloxy)-3-(isopropylamine)-butan-2-ol] and the β-adrenoceptor alkylating agent, pindobind, produced only small rightward shifts in the concentration-response curves of (-)-isoprenaline and (-)-trimetoquinol in this preparation. Rank order potency (pD2 values) of agonists was: (±)-trimetoquinol [1-(3',4',5'-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline] (8.34) = (-)-trimetoquinol (8.26) = BRL 37344 [R*R*)-(±)-4-[2'-{2-hydroxy-2-(3 -chrorophenyl)ethylamino}propyl]phenoxyacetic acid] (8.16) = ICI D7114 [(S)-4-(2-hydroxy-3-phenoxy-propylamino-ethoxy)-N-(2-methoxyethyl) phenoxyacetamide] (8.03) ≤ (-)-isoprenaline (7.82) > 3',5'-diiodotrimetoquinol [1-(3' ,5'-diiodo-4'-methoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline] (7.28) > 3'-iodotrimetoquinol [1-(3'-iodo-4',5'-dimethoxybenzyl)-6,7-dihydroxy- 1,2,3,4-tetrahydroisoquinoline] (7.04) > ractopamine (6.84) = 5,8-difluorotrimetoquinol [5,8-difluoro-6,7-dihydroxy-1-(3',4',5'-trimethoxybenzyl)-1,2,3,4 -tetrahydroisoquinoline] (6.82) > 8-fluorotrimetoquinol [6,7-dihydroxy-8-fluoro-1-(3',4',5'-trimethoxybenzyl)-1,2,3,4 -tetrahydroisoquinoline] (6.56) ≤ (-)-noradrenaline (6.46) ≤ (-)-adrenaline (6.36) > (±)-noradrenaline (6.24) > (±)-adrenaline (6.00) > clenbuterol (5.83) > (-)-1-benzyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (5.75). Isomeric activity ratios of trimetoquinol isomers [(-)-(S)- >> (+)-(R)-] in esophageal smooth muscle in the presence and absence of 1 μM pindolol were 1995- and 2951-fold, respectively; and were much greater than those in rat atria (282-fold) and rat trachea (107-fold). The atypical β/β3-adrenoceptor partial agonist, ICI D7114, produced concentration-dependent rightward shifts of the concentration-response curves of (-)-isoprenaline, (-)-trimetoquinol and the reference atypical β/β3-adrenoceptor agonist, BRL 37344. Schild plot analysis of ICI D7114 against trimetoquinol gave slope and pA2 values of 0.91 and of 7.9, respectively. These results clearly demonstrate that the relaxant effects of these agonists in rat esophageal smooth muscle are primarily mediated through the activation of atypical β/β3-adrenoceptors, (-)-Trimetoquinol was as potent as (-)-isoprenaline and BRL 37344, and was the most stereoselective agonist evaluated in this tissue system.

Original languageEnglish (US)
Pages (from-to)69-80
Number of pages12
JournalEuropean Journal of Pharmacology
Volume308
Issue number1
DOIs
StatePublished - Jul 11 1996

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Tretoquinol
Adrenergic Receptors
Smooth Muscle
Pharmacology
Isoproterenol
Pindolol
ractopamine
Epinephrine
Norepinephrine
Clenbuterol
Alkylating Agents
Trachea

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Pharmacological study of atypical β-adrenoceptors in rat esophageal smooth muscle. / Lezama, Edwin J.; Konkar, Anish A.; Salazar-Bookaman, M. Margarita; Miller, Duane; Feller, Dennis R.

In: European Journal of Pharmacology, Vol. 308, No. 1, 11.07.1996, p. 69-80.

Research output: Contribution to journalArticle

Lezama, Edwin J. ; Konkar, Anish A. ; Salazar-Bookaman, M. Margarita ; Miller, Duane ; Feller, Dennis R. / Pharmacological study of atypical β-adrenoceptors in rat esophageal smooth muscle. In: European Journal of Pharmacology. 1996 ; Vol. 308, No. 1. pp. 69-80.
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abstract = "The chemical specificity for the β-adrenoceptor mediated relaxation of rat esophageal smooth muscle was evaluated using selective and non-selective β-adrenoceptor agonists and antagonists. Pindolol, ICI 89,406, ICI 11855 [erythro-1-(7-methylindan-4-yloxy)-3-(isopropylamine)-butan-2-ol] and the β-adrenoceptor alkylating agent, pindobind, produced only small rightward shifts in the concentration-response curves of (-)-isoprenaline and (-)-trimetoquinol in this preparation. Rank order potency (pD2 values) of agonists was: (±)-trimetoquinol [1-(3',4',5'-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline] (8.34) = (-)-trimetoquinol (8.26) = BRL 37344 [R*R*)-(±)-4-[2'-{2-hydroxy-2-(3 -chrorophenyl)ethylamino}propyl]phenoxyacetic acid] (8.16) = ICI D7114 [(S)-4-(2-hydroxy-3-phenoxy-propylamino-ethoxy)-N-(2-methoxyethyl) phenoxyacetamide] (8.03) ≤ (-)-isoprenaline (7.82) > 3',5'-diiodotrimetoquinol [1-(3' ,5'-diiodo-4'-methoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline] (7.28) > 3'-iodotrimetoquinol [1-(3'-iodo-4',5'-dimethoxybenzyl)-6,7-dihydroxy- 1,2,3,4-tetrahydroisoquinoline] (7.04) > ractopamine (6.84) = 5,8-difluorotrimetoquinol [5,8-difluoro-6,7-dihydroxy-1-(3',4',5'-trimethoxybenzyl)-1,2,3,4 -tetrahydroisoquinoline] (6.82) > 8-fluorotrimetoquinol [6,7-dihydroxy-8-fluoro-1-(3',4',5'-trimethoxybenzyl)-1,2,3,4 -tetrahydroisoquinoline] (6.56) ≤ (-)-noradrenaline (6.46) ≤ (-)-adrenaline (6.36) > (±)-noradrenaline (6.24) > (±)-adrenaline (6.00) > clenbuterol (5.83) > (-)-1-benzyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (5.75). Isomeric activity ratios of trimetoquinol isomers [(-)-(S)- >> (+)-(R)-] in esophageal smooth muscle in the presence and absence of 1 μM pindolol were 1995- and 2951-fold, respectively; and were much greater than those in rat atria (282-fold) and rat trachea (107-fold). The atypical β/β3-adrenoceptor partial agonist, ICI D7114, produced concentration-dependent rightward shifts of the concentration-response curves of (-)-isoprenaline, (-)-trimetoquinol and the reference atypical β/β3-adrenoceptor agonist, BRL 37344. Schild plot analysis of ICI D7114 against trimetoquinol gave slope and pA2 values of 0.91 and of 7.9, respectively. These results clearly demonstrate that the relaxant effects of these agonists in rat esophageal smooth muscle are primarily mediated through the activation of atypical β/β3-adrenoceptors, (-)-Trimetoquinol was as potent as (-)-isoprenaline and BRL 37344, and was the most stereoselective agonist evaluated in this tissue system.",
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T1 - Pharmacological study of atypical β-adrenoceptors in rat esophageal smooth muscle

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AU - Konkar, Anish A.

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AU - Feller, Dennis R.

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N2 - The chemical specificity for the β-adrenoceptor mediated relaxation of rat esophageal smooth muscle was evaluated using selective and non-selective β-adrenoceptor agonists and antagonists. Pindolol, ICI 89,406, ICI 11855 [erythro-1-(7-methylindan-4-yloxy)-3-(isopropylamine)-butan-2-ol] and the β-adrenoceptor alkylating agent, pindobind, produced only small rightward shifts in the concentration-response curves of (-)-isoprenaline and (-)-trimetoquinol in this preparation. Rank order potency (pD2 values) of agonists was: (±)-trimetoquinol [1-(3',4',5'-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline] (8.34) = (-)-trimetoquinol (8.26) = BRL 37344 [R*R*)-(±)-4-[2'-{2-hydroxy-2-(3 -chrorophenyl)ethylamino}propyl]phenoxyacetic acid] (8.16) = ICI D7114 [(S)-4-(2-hydroxy-3-phenoxy-propylamino-ethoxy)-N-(2-methoxyethyl) phenoxyacetamide] (8.03) ≤ (-)-isoprenaline (7.82) > 3',5'-diiodotrimetoquinol [1-(3' ,5'-diiodo-4'-methoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline] (7.28) > 3'-iodotrimetoquinol [1-(3'-iodo-4',5'-dimethoxybenzyl)-6,7-dihydroxy- 1,2,3,4-tetrahydroisoquinoline] (7.04) > ractopamine (6.84) = 5,8-difluorotrimetoquinol [5,8-difluoro-6,7-dihydroxy-1-(3',4',5'-trimethoxybenzyl)-1,2,3,4 -tetrahydroisoquinoline] (6.82) > 8-fluorotrimetoquinol [6,7-dihydroxy-8-fluoro-1-(3',4',5'-trimethoxybenzyl)-1,2,3,4 -tetrahydroisoquinoline] (6.56) ≤ (-)-noradrenaline (6.46) ≤ (-)-adrenaline (6.36) > (±)-noradrenaline (6.24) > (±)-adrenaline (6.00) > clenbuterol (5.83) > (-)-1-benzyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (5.75). Isomeric activity ratios of trimetoquinol isomers [(-)-(S)- >> (+)-(R)-] in esophageal smooth muscle in the presence and absence of 1 μM pindolol were 1995- and 2951-fold, respectively; and were much greater than those in rat atria (282-fold) and rat trachea (107-fold). The atypical β/β3-adrenoceptor partial agonist, ICI D7114, produced concentration-dependent rightward shifts of the concentration-response curves of (-)-isoprenaline, (-)-trimetoquinol and the reference atypical β/β3-adrenoceptor agonist, BRL 37344. Schild plot analysis of ICI D7114 against trimetoquinol gave slope and pA2 values of 0.91 and of 7.9, respectively. These results clearly demonstrate that the relaxant effects of these agonists in rat esophageal smooth muscle are primarily mediated through the activation of atypical β/β3-adrenoceptors, (-)-Trimetoquinol was as potent as (-)-isoprenaline and BRL 37344, and was the most stereoselective agonist evaluated in this tissue system.

AB - The chemical specificity for the β-adrenoceptor mediated relaxation of rat esophageal smooth muscle was evaluated using selective and non-selective β-adrenoceptor agonists and antagonists. Pindolol, ICI 89,406, ICI 11855 [erythro-1-(7-methylindan-4-yloxy)-3-(isopropylamine)-butan-2-ol] and the β-adrenoceptor alkylating agent, pindobind, produced only small rightward shifts in the concentration-response curves of (-)-isoprenaline and (-)-trimetoquinol in this preparation. Rank order potency (pD2 values) of agonists was: (±)-trimetoquinol [1-(3',4',5'-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline] (8.34) = (-)-trimetoquinol (8.26) = BRL 37344 [R*R*)-(±)-4-[2'-{2-hydroxy-2-(3 -chrorophenyl)ethylamino}propyl]phenoxyacetic acid] (8.16) = ICI D7114 [(S)-4-(2-hydroxy-3-phenoxy-propylamino-ethoxy)-N-(2-methoxyethyl) phenoxyacetamide] (8.03) ≤ (-)-isoprenaline (7.82) > 3',5'-diiodotrimetoquinol [1-(3' ,5'-diiodo-4'-methoxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline] (7.28) > 3'-iodotrimetoquinol [1-(3'-iodo-4',5'-dimethoxybenzyl)-6,7-dihydroxy- 1,2,3,4-tetrahydroisoquinoline] (7.04) > ractopamine (6.84) = 5,8-difluorotrimetoquinol [5,8-difluoro-6,7-dihydroxy-1-(3',4',5'-trimethoxybenzyl)-1,2,3,4 -tetrahydroisoquinoline] (6.82) > 8-fluorotrimetoquinol [6,7-dihydroxy-8-fluoro-1-(3',4',5'-trimethoxybenzyl)-1,2,3,4 -tetrahydroisoquinoline] (6.56) ≤ (-)-noradrenaline (6.46) ≤ (-)-adrenaline (6.36) > (±)-noradrenaline (6.24) > (±)-adrenaline (6.00) > clenbuterol (5.83) > (-)-1-benzyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (5.75). Isomeric activity ratios of trimetoquinol isomers [(-)-(S)- >> (+)-(R)-] in esophageal smooth muscle in the presence and absence of 1 μM pindolol were 1995- and 2951-fold, respectively; and were much greater than those in rat atria (282-fold) and rat trachea (107-fold). The atypical β/β3-adrenoceptor partial agonist, ICI D7114, produced concentration-dependent rightward shifts of the concentration-response curves of (-)-isoprenaline, (-)-trimetoquinol and the reference atypical β/β3-adrenoceptor agonist, BRL 37344. Schild plot analysis of ICI D7114 against trimetoquinol gave slope and pA2 values of 0.91 and of 7.9, respectively. These results clearly demonstrate that the relaxant effects of these agonists in rat esophageal smooth muscle are primarily mediated through the activation of atypical β/β3-adrenoceptors, (-)-Trimetoquinol was as potent as (-)-isoprenaline and BRL 37344, and was the most stereoselective agonist evaluated in this tissue system.

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