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

Lezama, E; Konkar, Anish; Margarita^Salazar-Bookaman, M.; Miller, Duane D.; Feller, Dennis R.

doi:10.1016/0014-2999(96)00236-1

Cited by 23 publications

(11 citation statements)

References 20 publications

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“…These potencies with CL 316243 and other selective ␤ 3 -agonists are similar to those in vivo studies in the LES (DiMarino et al, 2002), in the cardiovascular smooth muscles (Gauthier et al, 2000), in vitro studies in human detrusor smooth muscle (Igawa et al, 1999), and in rat esophageal muscularis mucosa (de Boer et al, 1993). The effects of certain ␤ 3 -selective agonists in other smooth muscles may be either of comparable or of higher potency than of ␤ 1 -and ␤ 2 -agonists (Lezama et al, 1996;Roberts et al, 1999). It is noteworthy that the smooth muscles examined in the previous studies were not spontaneously tonic.…”

Section: Discussionsupporting

confidence: 75%

Inhibitory Effect of β₃-Adrenoceptor Agonist in Lower Esophageal Sphincter Smooth Muscle: In Vitro Studies

Sarma

Banwait²,

Basak³

et al. 2003

J Pharmacol Exp Ther

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We investigated the effects of (R,R)-5-[2-[2-3-chlorophenyl)-2-hydroxyethyl] -amino]propyl] -1,3 -benzodioxole -2 , 2 -dicarboxylate (CL 316243) (a typical ␤ 3 -agonist) on the spontaneously tonic smooth muscle of the lower esophageal sphincter (LES). Studies were carried out in smooth muscle strips and smooth muscle cells (SMCs) of opossum LES. Isometric tension was recorded in the basal state and after CL 316243, and before and after) and nonselective antagonist propranolol. In some experiments, the effects of nonadrenergic noncholinergic (NANC) nerve activation by electrical field stimulation (EFS) were also examined. The effects of CL 316243 were compared with those of nonselective ␤-agonist isoproterenol. CL 316243 caused a concentration-dependent relaxation of the LES smooth muscle. The relaxant action of CL 316243 was determined to be directly at the smooth muscle because it remained unmodified by the neurotoxin tetrodotoxin and other neurohumoral antagonists, and also was observed in the SMCs. L 748337 selectively antagonized the relaxant effect of CL 316243 and, conversely, had no significant effect on the inhibitory actions of isoproterenol. CL 316243 (1 ϫ 10 Ϫ8 M) caused an augmentation of NANC relaxation in the LES. Another ␤ 3 -agonist, (S)-4-[hydroxy-3-phenoxy-propylamino-ethoxy]-N-(2-methoxyethyl)-phenoxyacetamide (ZD 7114), also caused concentration-dependent full relaxation of the LES that was selectively antagonized by ␤ 3 -anatagonist 3-(2-ethylphenoxy)-1-[(1S)1,2,3,4-tetrahydronaphth-1-ylaminol]-(2S)-2-propanol oxalate (SR 59230A). These studies defined the effects of characteristic inhibitory ␤ 3 -adrenoceptors in the spontaneously tonic LES smooth muscle and suggested a potential therapeutic role in the esophageal motility disorders characterized by hypertensive LES.

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Section: Discussionsupporting

confidence: 75%

Inhibitory Effect of β₃-Adrenoceptor Agonist in Lower Esophageal Sphincter Smooth Muscle: In Vitro Studies

Sarma

Banwait²,

Basak³

et al. 2003

J Pharmacol Exp Ther

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“…The parent tetrahydroisoquinoline, TMQ, was a potent nonselective activator of both human ß 1 -and ß 3 -AR subtypes, and this finding is similar to our previous results on rat ß-AR subtypes [17][18][19]. We next examined effects of iodine substitution at the 1-benzyl ring of TMQ on ß-AR activity, since such substitutions potently activated rat ß 3 -AR [17][18][19].…”

Section: Effect Of Replacing 1-benzyl Ring Of Tmq On ß-Ar Activitysupporting

confidence: 64%

“…TMQ, a prototypical tetrahydroisoquinoline, potently activates ß-AR subtypes in rat tissues [17][18][19][20]. Both TMQ and isoproterenol potently activated both human ß 1 -and ß 3 -AR subtypes in cAMP accumulation assays (table 1).…”

Section: ß-Ar Activities Of Tmq and Reference Compoundsmentioning

confidence: 99%

“…We next examined effects of iodine substitution at the 1-benzyl ring of TMQ on ß-AR activity, since such substitutions potently activated rat ß 3 -AR [17][18][19]. Iodine substituents were well tolerated at both ß 1 -and ß 3 -AR with a modest increase in affinity for both ß-AR subtypes as compared to TMQ.…”

Section: Effect Of Replacing 1-benzyl Ring Of Tmq On ß-Ar Activitymentioning

confidence: 99%

“…1-Benzyl ring halogen-substituted analogs of TMQ stimulate ß 3 -AR with a higher potency than ß 1 -AR and are partial agonists of ß 2 -AR [16,17,19,21]. Significantly, 1-benzyl iodine-substituted analogs of TMQ stimulate the rat ß 3 -AR with high efficacy and potency [17][18][19]. As noted above, activities observed at rat ß 3 -AR do not translate to similar activities at the human ß 3 -AR.…”

Section: Introductionmentioning

confidence: 99%

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Biochemical Activities of Trimetoquinol Analogs at Human β<sub>1</sub>- and β<sub>3</sub>-Adrenergic Receptors

Konkar

Nikulin²,

Angeles³

et al. 2001

Pharmacology

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The biochemical activities of trimetoquinol (TMQ) analogs were evaluated at the human β₁- and β₃-adrenergic receptor (AR) subtypes expressed in Chinese hamster ovary cells. In radioligand binding assays, the 1-benzyl iodine-substituted analogs exhibited higher binding affinities at both β₁- and β₃-AR subtype as compared to TMQ. In cAMP accumulation assays, these analogs exhibited high potencies at both β₁- and β₃-AR. The 3′,5′-diiodo-4′-amino analog of TMQ was the most potent β₃-AR agonist, 17-fold more potent at the β₃-AR versus the β₁-AR. Masking of the 6,7-dihydroxy group of the catechol ring of 3′,5′-diiodo-4′-acetamido analog of TMQ, a potent β₁- and β₃-AR agonist, abolished activity at both β-AR subtypes. Furthermore, substitution of a strong electron withdrawing group such as the trifluoromethyl moiety at the 1-benzyl ring of TMQ dramatically decreased potency at β₁- and β₃-AR compared to TMQ. Replacement of the 1-benzyl ring of TMQ with a naphthalene ring did not alter affinity but reduced potency of resulting 1-naphthylmethyl and 2-naphthylmethyl analogs at β₁- and β₃-AR compared to TMQ. Our results define the structural and electronic properties of substituents on TMQ necessary for potent activation of β₁- and β₃-AR and suggest that further modifications of the 1-benzyl iodine-substituted analogs may yield potent β₃-AR agonists.

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Activity on the gastrointestinal tract1

Vogel¹,

Vogel²,

Schölkens³

et al. 2002

Drug Discovery and Evaluation

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

Cited by 23 publications

References 20 publications

Inhibitory Effect of β₃-Adrenoceptor Agonist in Lower Esophageal Sphincter Smooth Muscle: In Vitro Studies

Inhibitory Effect of β₃-Adrenoceptor Agonist in Lower Esophageal Sphincter Smooth Muscle: In Vitro Studies

Biochemical Activities of Trimetoquinol Analogs at Human β<sub>1</sub>- and β<sub>3</sub>-Adrenergic Receptors

Activity on the gastrointestinal tract1

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

Cited by 23 publications

References 20 publications

Inhibitory Effect of β3-Adrenoceptor Agonist in Lower Esophageal Sphincter Smooth Muscle: In Vitro Studies

Inhibitory Effect of β3-Adrenoceptor Agonist in Lower Esophageal Sphincter Smooth Muscle: In Vitro Studies

Biochemical Activities of Trimetoquinol Analogs at Human β<sub>1</sub>- and β<sub>3</sub>-Adrenergic Receptors

Activity on the gastrointestinal tract1

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Inhibitory Effect of β₃-Adrenoceptor Agonist in Lower Esophageal Sphincter Smooth Muscle: In Vitro Studies

Inhibitory Effect of β₃-Adrenoceptor Agonist in Lower Esophageal Sphincter Smooth Muscle: In Vitro Studies