Stereoselective interaction of tetrahydroisoquinolines in β-adrenoceptor systems

Michael T. Piascik; Peter Osei-Gyimah; Duane D. Miller; Dennis R. Feller

doi:10.1016/0014-2999(78)90166-8

Stereoselective interaction of tetrahydroisoquinolines in β-adrenoceptor systems

Michael T. Piascik, Peter Osei-Gyimah, Duane D. Miller, Dennis R. Feller

Pharmacology and Nutritional Sciences

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

In selected β₁- (heart, lipolysis) and β₂-adrenoceptor (trachea) systems, the interaction of racemic-trimetoquinol (TMQ) and the erythro- and threo-diastereomers of 1-(3′,4′,5′-trimethoxy-α-hydroxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (α-hydroxy TMQ) was investigated. Each tetrahydroisoquinoline possessed agonist activity in these β-adrenoceptor systems. The rank order of potency observed for these compounds was racemic-TMQ > erythro-α-hydroxy TMQ > threo-α-hydroxy TMQ. Using isolated fat adipocytes, a favorable correlation was observed between the elevation in c-AMP and pharmacological response for the TMQ stereoisomers and diastereomers of α-hydroxy TMQ. The rise in intracellular c-AMP produced by (-)- and (+)-TMQ in fat cells was blocked by the presence of propranolol, and not in the presence of phentolamine. Since considerably higher concentrations (>10^-4 M) of these compounds were required to produce a significant inhibition of c-AMP phosphodiesterase activity in adipose tissue, it is proposed that the lipolytic response is a result of stereoselective interaction of these tetrahydroisoquinolines at the level of membrane-bound adenylate cyclase.

Original language	English
Pages (from-to)	393-401
Number of pages	9
Journal	European Journal of Pharmacology
Volume	48
Issue number	4
DOIs	https://doi.org/10.1016/0014-2999(78)90166-8
State	Published - Apr 15 1978

Bibliographical note

Funding Information:
This study was supported in part by a grant from the National Institutes of Health, USPHS (NS 10896). One of us (M.T.P.) is a Fellow of the American Foundation for Pharmaceutical Education. We also thank Dr. Popat Patil for his constructive comments in the design of these studies, and Mrs. Raji Ra-man for her technical assistance.

Funding

This study was supported in part by a grant from the National Institutes of Health, USPHS (NS 10896). One of us (M.T.P.) is a Fellow of the American Foundation for Pharmaceutical Education. We also thank Dr. Popat Patil for his constructive comments in the design of these studies, and Mrs. Raji Ra-man for her technical assistance.

Funders	Funder number
National Institutes of Health (NIH)
U.S. Public Health Service	NS 10896

Keywords

Diastereomers
Stereoisomers
Trimetoquinol
cAMP
α-Hydroxytrimetoquinol
β-Adrenoceptors

ASJC Scopus subject areas

Pharmacology

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10.1016/0014-2999(78)90166-8

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@article{89ab41a6a5a645139cf3e75479ccced3,

title = "Stereoselective interaction of tetrahydroisoquinolines in β-adrenoceptor systems",

abstract = "In selected β1- (heart, lipolysis) and β2-adrenoceptor (trachea) systems, the interaction of racemic-trimetoquinol (TMQ) and the erythro- and threo-diastereomers of 1-(3′,4′,5′-trimethoxy-α-hydroxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (α-hydroxy TMQ) was investigated. Each tetrahydroisoquinoline possessed agonist activity in these β-adrenoceptor systems. The rank order of potency observed for these compounds was racemic-TMQ > erythro-α-hydroxy TMQ > threo-α-hydroxy TMQ. Using isolated fat adipocytes, a favorable correlation was observed between the elevation in c-AMP and pharmacological response for the TMQ stereoisomers and diastereomers of α-hydroxy TMQ. The rise in intracellular c-AMP produced by (-)- and (+)-TMQ in fat cells was blocked by the presence of propranolol, and not in the presence of phentolamine. Since considerably higher concentrations (>10-4 M) of these compounds were required to produce a significant inhibition of c-AMP phosphodiesterase activity in adipose tissue, it is proposed that the lipolytic response is a result of stereoselective interaction of these tetrahydroisoquinolines at the level of membrane-bound adenylate cyclase.",

keywords = "Diastereomers, Stereoisomers, Trimetoquinol, cAMP, α-Hydroxytrimetoquinol, β-Adrenoceptors",

author = "Piascik, \{Michael T.\} and Peter Osei-Gyimah and Miller, \{Duane D.\} and Feller, \{Dennis R.\}",

note = "Funding Information: This study was supported in part by a grant from the National Institutes of Health, USPHS (NS 10896). One of us (M.T.P.) is a Fellow of the American Foundation for Pharmaceutical Education. We also thank Dr. Popat Patil for his constructive comments in the design of these studies, and Mrs. Raji Ra-man for her technical assistance.",

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AU - Osei-Gyimah, Peter

AU - Miller, Duane D.

AU - Feller, Dennis R.

N1 - Funding Information: This study was supported in part by a grant from the National Institutes of Health, USPHS (NS 10896). One of us (M.T.P.) is a Fellow of the American Foundation for Pharmaceutical Education. We also thank Dr. Popat Patil for his constructive comments in the design of these studies, and Mrs. Raji Ra-man for her technical assistance.

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N2 - In selected β1- (heart, lipolysis) and β2-adrenoceptor (trachea) systems, the interaction of racemic-trimetoquinol (TMQ) and the erythro- and threo-diastereomers of 1-(3′,4′,5′-trimethoxy-α-hydroxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (α-hydroxy TMQ) was investigated. Each tetrahydroisoquinoline possessed agonist activity in these β-adrenoceptor systems. The rank order of potency observed for these compounds was racemic-TMQ > erythro-α-hydroxy TMQ > threo-α-hydroxy TMQ. Using isolated fat adipocytes, a favorable correlation was observed between the elevation in c-AMP and pharmacological response for the TMQ stereoisomers and diastereomers of α-hydroxy TMQ. The rise in intracellular c-AMP produced by (-)- and (+)-TMQ in fat cells was blocked by the presence of propranolol, and not in the presence of phentolamine. Since considerably higher concentrations (>10-4 M) of these compounds were required to produce a significant inhibition of c-AMP phosphodiesterase activity in adipose tissue, it is proposed that the lipolytic response is a result of stereoselective interaction of these tetrahydroisoquinolines at the level of membrane-bound adenylate cyclase.

AB - In selected β1- (heart, lipolysis) and β2-adrenoceptor (trachea) systems, the interaction of racemic-trimetoquinol (TMQ) and the erythro- and threo-diastereomers of 1-(3′,4′,5′-trimethoxy-α-hydroxybenzyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (α-hydroxy TMQ) was investigated. Each tetrahydroisoquinoline possessed agonist activity in these β-adrenoceptor systems. The rank order of potency observed for these compounds was racemic-TMQ > erythro-α-hydroxy TMQ > threo-α-hydroxy TMQ. Using isolated fat adipocytes, a favorable correlation was observed between the elevation in c-AMP and pharmacological response for the TMQ stereoisomers and diastereomers of α-hydroxy TMQ. The rise in intracellular c-AMP produced by (-)- and (+)-TMQ in fat cells was blocked by the presence of propranolol, and not in the presence of phentolamine. Since considerably higher concentrations (>10-4 M) of these compounds were required to produce a significant inhibition of c-AMP phosphodiesterase activity in adipose tissue, it is proposed that the lipolytic response is a result of stereoselective interaction of these tetrahydroisoquinolines at the level of membrane-bound adenylate cyclase.

KW - Diastereomers

KW - Stereoisomers

KW - Trimetoquinol

KW - cAMP

KW - α-Hydroxytrimetoquinol

KW - β-Adrenoceptors

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VL - 48

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JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

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ER -

Stereoselective interaction of tetrahydroisoquinolines in β-adrenoceptor systems

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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