Bronchoselective actions of a new series of trimetoquinol analogues

Asoke Mukhopadhyay, Douglas J. Sober, Jane Chang, Richard T. Slenn, Hebattalla M. Amin, Duane Miller, Dennis R. Feller

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Abstract

In selected β1-(guinea pig atria) and β2-(guinea pig trachea and lung parenchyma) adrenoceptor systems, we have examined the interaction of isoproterenol (ISO), trimetoquinol (TMQ), erythro- and threo-diastereoisomers of 1-(3,4,5-trimethoxy-α-methylbenzyl)-6,7-dihydroxy- 1,2,3,4-tetrahydroisoquinoline (α-methylTMQ), α-dimethylTMQ, N-methylTMQ and N-[2-methyl-2-(3,4,5- trimethoxyphenyl)propyl]dopamine (open chain dimethylTMQ analogue). The rank order of potency for agonists in trachea was threo-α-methylTMQ>(±)-TMQ>ISO>erythro-α-methylTMQ>N-methylTMQ>α-dimethylTMQ. Only N-methylTMQ gave an intrinsic activity similar to ISO, whereas the α-methylated TMQ analogues were partial agonists in this β2-system. In atria, the rank order of β1-potency was ISO>(±)-TMQ>threo-α-methylTMQ>N-methylTMQ=erythro-α-methylTMQ. Maximal chronotr effects of all compounds, with the exception of threo-α-methylTMQ, were similar to ISO in this preparation. Both α-dimethylTMQ and open chain dimethylTMQ analogues were inactive as agagonists in this β1-system. The ratio of β21 selectivity (trach atria), relative to ISO for threo-α-methylTMQ, erythro-α-methylTMQ, TMQ and N-methylTMQ was 106.5, 27, 7 and 5.8, respectively. Whereas the rank order of potency for selected compounds in lung parenchyma was ISO>threo-α-methylTMQ=TMQ>erythro-α- methylTMQ, the comparative β2-selectivity (lung parenchyma vs. atria) relative to ISO, for erythro-α-methylTMQ, threo-α-methylTM and TMQ was 2.5, 1.9 and 0.24, respectively. It is concluded that lipophilic substitutions on the α-carbon of the 1-(3,4,5- trimethoxybenzyl)-substituent of TMQ can generate compounds which are potent bronchoselective adrenoceptor agonists. Threo-α- methylTMQ and erythro-α-methylTMQ were more β2-selective than (±)-TMQ.

Original languageEnglish (US)
Pages (from-to)209-219
Number of pages11
JournalEuropean Journal of Pharmacology
Volume77
Issue number4
DOIs
StatePublished - Feb 5 1982

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Tretoquinol
Isoproterenol
Trachea
Lung
Adrenergic Receptors
Guinea Pigs
Dopamine
Carbon

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Mukhopadhyay, A., Sober, D. J., Chang, J., Slenn, R. T., Amin, H. M., Miller, D., & Feller, D. R. (1982). Bronchoselective actions of a new series of trimetoquinol analogues. European Journal of Pharmacology, 77(4), 209-219. https://doi.org/10.1016/0014-2999(82)90121-2

Bronchoselective actions of a new series of trimetoquinol analogues. / Mukhopadhyay, Asoke; Sober, Douglas J.; Chang, Jane; Slenn, Richard T.; Amin, Hebattalla M.; Miller, Duane; Feller, Dennis R.

In: European Journal of Pharmacology, Vol. 77, No. 4, 05.02.1982, p. 209-219.

Research output: Contribution to journalArticle

Mukhopadhyay, A, Sober, DJ, Chang, J, Slenn, RT, Amin, HM, Miller, D & Feller, DR 1982, 'Bronchoselective actions of a new series of trimetoquinol analogues', European Journal of Pharmacology, vol. 77, no. 4, pp. 209-219. https://doi.org/10.1016/0014-2999(82)90121-2
Mukhopadhyay, Asoke ; Sober, Douglas J. ; Chang, Jane ; Slenn, Richard T. ; Amin, Hebattalla M. ; Miller, Duane ; Feller, Dennis R. / Bronchoselective actions of a new series of trimetoquinol analogues. In: European Journal of Pharmacology. 1982 ; Vol. 77, No. 4. pp. 209-219.
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abstract = "In selected β1-(guinea pig atria) and β2-(guinea pig trachea and lung parenchyma) adrenoceptor systems, we have examined the interaction of isoproterenol (ISO), trimetoquinol (TMQ), erythro- and threo-diastereoisomers of 1-(3,4,5-trimethoxy-α-methylbenzyl)-6,7-dihydroxy- 1,2,3,4-tetrahydroisoquinoline (α-methylTMQ), α-dimethylTMQ, N-methylTMQ and N-[2-methyl-2-(3,4,5- trimethoxyphenyl)propyl]dopamine (open chain dimethylTMQ analogue). The rank order of potency for agonists in trachea was threo-α-methylTMQ>(±)-TMQ>ISO>erythro-α-methylTMQ>N-methylTMQ>α-dimethylTMQ. Only N-methylTMQ gave an intrinsic activity similar to ISO, whereas the α-methylated TMQ analogues were partial agonists in this β2-system. In atria, the rank order of β1-potency was ISO>(±)-TMQ>threo-α-methylTMQ>N-methylTMQ=erythro-α-methylTMQ. Maximal chronotr effects of all compounds, with the exception of threo-α-methylTMQ, were similar to ISO in this preparation. Both α-dimethylTMQ and open chain dimethylTMQ analogues were inactive as agagonists in this β1-system. The ratio of β2:β1 selectivity (trach atria), relative to ISO for threo-α-methylTMQ, erythro-α-methylTMQ, TMQ and N-methylTMQ was 106.5, 27, 7 and 5.8, respectively. Whereas the rank order of potency for selected compounds in lung parenchyma was ISO>threo-α-methylTMQ=TMQ>erythro-α- methylTMQ, the comparative β2-selectivity (lung parenchyma vs. atria) relative to ISO, for erythro-α-methylTMQ, threo-α-methylTM and TMQ was 2.5, 1.9 and 0.24, respectively. It is concluded that lipophilic substitutions on the α-carbon of the 1-(3,4,5- trimethoxybenzyl)-substituent of TMQ can generate compounds which are potent bronchoselective adrenoceptor agonists. Threo-α- methylTMQ and erythro-α-methylTMQ were more β2-selective than (±)-TMQ.",
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N2 - In selected β1-(guinea pig atria) and β2-(guinea pig trachea and lung parenchyma) adrenoceptor systems, we have examined the interaction of isoproterenol (ISO), trimetoquinol (TMQ), erythro- and threo-diastereoisomers of 1-(3,4,5-trimethoxy-α-methylbenzyl)-6,7-dihydroxy- 1,2,3,4-tetrahydroisoquinoline (α-methylTMQ), α-dimethylTMQ, N-methylTMQ and N-[2-methyl-2-(3,4,5- trimethoxyphenyl)propyl]dopamine (open chain dimethylTMQ analogue). The rank order of potency for agonists in trachea was threo-α-methylTMQ>(±)-TMQ>ISO>erythro-α-methylTMQ>N-methylTMQ>α-dimethylTMQ. Only N-methylTMQ gave an intrinsic activity similar to ISO, whereas the α-methylated TMQ analogues were partial agonists in this β2-system. In atria, the rank order of β1-potency was ISO>(±)-TMQ>threo-α-methylTMQ>N-methylTMQ=erythro-α-methylTMQ. Maximal chronotr effects of all compounds, with the exception of threo-α-methylTMQ, were similar to ISO in this preparation. Both α-dimethylTMQ and open chain dimethylTMQ analogues were inactive as agagonists in this β1-system. The ratio of β2:β1 selectivity (trach atria), relative to ISO for threo-α-methylTMQ, erythro-α-methylTMQ, TMQ and N-methylTMQ was 106.5, 27, 7 and 5.8, respectively. Whereas the rank order of potency for selected compounds in lung parenchyma was ISO>threo-α-methylTMQ=TMQ>erythro-α- methylTMQ, the comparative β2-selectivity (lung parenchyma vs. atria) relative to ISO, for erythro-α-methylTMQ, threo-α-methylTM and TMQ was 2.5, 1.9 and 0.24, respectively. It is concluded that lipophilic substitutions on the α-carbon of the 1-(3,4,5- trimethoxybenzyl)-substituent of TMQ can generate compounds which are potent bronchoselective adrenoceptor agonists. Threo-α- methylTMQ and erythro-α-methylTMQ were more β2-selective than (±)-TMQ.

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