Bronchoselective actions of a new series of trimetoquinol analogues

Mukhopadhyay, A.; Sober, Douglas J.; Chang, Jong Sun; Slenn, Richard T.; Amin, Hebattalla M.; Miller, Duane D.; Feller, Dennis R.

doi:10.1016/0014-2999(82)90121-2

Cited by 14 publications

(3 citation statements)

References 25 publications

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“…These results agree with previously reported 3-and 7-fold p2/p1selectivities of this isomer. 12, 29 Interestingly, the IAR values showed 7.1-and 3.4-fold differences in favor of trachedung versus atridventricle, respectively. In this regard, the experimentally determined IARs for the TMQ isomers on tracheal and esophageal smooth muscle relaxation, chronotropism (atria), and lipolysis (brown adipose tissue) are similar to that…”

Section: Discussionmentioning

confidence: 97%

“…which varied between 36and 62-fold.6712. 29 We attribute these IAR discrepancies in part to differences in p-AR populations, tissue pretreatments, or enantiomeric purity. Further, only a few studies have attempted to correlate the functional effects of TMQ analogs to biochemical measurements such as receptor bindi1-12~ and CAMP a~c u m u l a t i o n~~'~~~~~~~ in p-ARcontaining tissues, and to our knowledge, no work using the enantiomers of TMQ in various P-subtypes has appeared in the literature.…”

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confidence: 99%

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Isomeric‐Activity ratios of trimetoquinol enantiomers on β‐adrenergic receptor subtypes: Functional and biochemical studies

et al. 1994

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Trimetoquinol [1-(3',4',5'-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4- tetrahydroisoquinoline , TMQ] exists as two enantiomers, and the (-)-(S)-isomer is a potent beta-adrenergic receptor (beta-AR) agonist. Experiments were conducted to examine the functional and biochemical potencies of the (S)-and (R)-enantiomers of TMQ for interaction with beta-AR subtypes in tissues, membrane fractions, and cell systems. The isomeric-activity ratios (IARs) of the TMQ isomers [(S)-isomer > > (R)-isomer] for stimulation of beta 1- and beta 2-AR of guinea pig right atria and trachea were 224 and 1585, respectively; these IARs were similar to those observed on atypical beta-AR systems of rat distal colon (575), rat brown adipocytes (398), but differed from that of rat esophageal smooth muscle (2884) in the presence of pindolol. In the absence of pindolol, the potencies for the TMQ enantiomers were slightly increased; however, the IARs remained unchanged in rat distal colon, rat brown adipocytes, and rat esophageal smooth muscle. Similarly, radioligand binding studies demonstrated that the TMQ isomer beta-AR affinities were stereoselective for the (-)-(S)-isomer in membranes of guinea pig left ventricle (beta 1) and lung (beta 2) giving IARs of 115 and 389, respectively; and in E. coli expressing human beta 1- and beta 2-AR giving IARs of 661 and 724, respectively. Corresponding IARs of receptor affinities and stimulation of cAMP accumulation in Chinese hamster ovary cells expressing human beta 2-AR and rat beta 3-AR were 331 and 282, and 118 and 4678, respectively. These results indicate that the (-)-(S)-isomer of TMQ exhibits high affinity, and is a potent and highly stereoselective agonist for each beta-AR subtype, that the isomers generally fail to differentiate between the beta-AR subtypes, and that, based upon differences in IAR within beta 3-AR containing systems, subtypes of atypical beta (or beta 3)-AR may exist in adipose tissue and smooth muscle.

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Section: Discussionmentioning

confidence: 97%

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confidence: 99%

Isomeric‐Activity ratios of trimetoquinol enantiomers on β‐adrenergic receptor subtypes: Functional and biochemical studies

et al. 1994

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“…Concentrated H2S04 (0.2 mL) was added to this solution and the resulting mixture was heated at reflux for 7 h. It was cooled to 20 °C, poured into cold H20, and extracted with Et20. The ethereal extract was dried, filtered, and evaporated to yield 17 (2.80 g, 72%) as an oil: NMR 8 2.3-2.7 (2 H, m), 2.9-3.3 (2 H, m), 3.32 (6 H, s), 3.70 (3 H, s), 5.44 (H, s), 7.30 (H, d, J = 2 Hz), 7.44 (H, d, J = 2 Hz).…”

Section: -Bromo-l-fluoro-2-[[[(ll-dimethylethylmentioning

confidence: 99%

3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. 3. 7-(3,5-Disubstituted-[1,1'-biphenyl]-2-yl)-3,5-dihydroxy-6-heptenoic acids and their lactone derivatives

Stokker¹,

Alberts²,

Anderson³

et al. 1986

J. Med. Chem.

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The syntheses of a series of 7-(3,5-disubstituted [1,1'-bephenyl]-2-yl)-3,5-dihydroxy-6-heptenoic acids and their lactones are reported. Intrinsic 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitory activity is enhanced markedly when the biphenyl moiety is substituted by chloro or methyl groups at positions 3 and 5 and a fluoro group at position 4'. These substitutions, followed by resolution, provided compounds 100(+) and 110(+) with 2.8 times the intrinsic inhibitory activity of compactin. Compound 100(+) was shown to possess the same chirality in the lactone ring as compactin by single-crystal X-ray crystallography.

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Antiallergic effect of trimetoquinol analogs on actively sensitized guinea pig lung tissue, in vitro

Mukhopadhyay

Miller

Feller

1986

Biochemical Pharmacology

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Bronchoselective actions of a new series of trimetoquinol analogues

Cited by 14 publications

References 25 publications

Isomeric‐Activity ratios of trimetoquinol enantiomers on β‐adrenergic receptor subtypes: Functional and biochemical studies

Isomeric‐Activity ratios of trimetoquinol enantiomers on β‐adrenergic receptor subtypes: Functional and biochemical studies

3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. 3. 7-(3,5-Disubstituted-[1,1'-biphenyl]-2-yl)-3,5-dihydroxy-6-heptenoic acids and their lactone derivatives

Antiallergic effect of trimetoquinol analogs on actively sensitized guinea pig lung tissue, in vitro

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