Influence of substituted tetrahydroisoquinolines and catecholamines on lipolysis, in vitro-II. Stereoselectivity

R. F. Shonk, Duane Miller, D. R. Feller

Research output: Contribution to journalArticle

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Abstract

Utilizing glycerol release as an index of lipolysis in rat epididymal fat tissue, intrinsic activity and affinity (pD2 values) constants were calculated for various tetrahydroisoquinoline (THI) and catecholamine derivatives. Differences were noted in the pD2 values and to a lesser degree in the intrinsic activity constants of the d-l-isomers and deoxy derivatives of the agonists studied. In all cases, the l-isomers proved to be more active than the d-isomers or deoxy derivatives in the release of glycerol from adipose tissue, in vitro. Significant differences in the pD2 values for the more potent l-isomers were calculated and the rank order was observed to be 1-(3′,4′,5′-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-THI > isoproterenol > norepinephrine ≥ 1-benzyl-6,7-dihydroxy-1,2,3,4-THI. The deoxy derivatives of isoproterenol and norepinephrine possessed nearly identical pD2 values to their respective d-isomers. N-isopropyldopamine and dopamine, however, were unable to elicit a maximum lipolytic response and did not possess equivalent intrinsic activity constants to d-isoproterenol and d-norepinephrine. Propranolol inhibited the lipolysis induced by 1-(3′,4′,5′-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-THI and norepinephrine in a competitive manner, whereas a noncompetitive inhibition was observed in the presence of the alpha-antagonist, phentolamine. The activity-differences for the isomers of 1-(3′,4′,5′-trimethoxybenzyl)-6,7-dihydroxy-1,2,3,4-THI (795-fold) and isoproterenol (316-fold) were clearly greater than the isomeric-activity differences observed for norepinephrine (100-fold) and 1-benzyl-6, 7-dihydroxy-1,2,3,4-THI (25-fold). These results indicate: (a) that the THI derivatives which do not possess an alcoholic (μ-hydroxyl) group on the ethylamino-side chain are potent lipolytic agonists, and (b) that the tetrahydroisoquinoline derivatives act at a receptor system in adipose tissue similar, if not identical, to the interaction observed with norepinephrine. It may be suggested, therefore, that the μ-hydroxyl group is not a necessary requirement for potent lipolytic activity as previously believed.

Original languageEnglish (US)
Pages (from-to)3403-3412
Number of pages10
JournalBiochemical Pharmacology
Volume20
Issue number12
DOIs
StatePublished - Jan 1 1971

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Tetrahydroisoquinolines
Stereoselectivity
Lipolysis
Isomers
Catecholamines
Norepinephrine
Derivatives
Isoproterenol
Tissue
Hydroxyl Radical
Glycerol
Adipose Tissue
Phentolamine
Propranolol
In Vitro Techniques
Rats
Dopamine
Fats
1,2,3,4-tetrahydroisoquinoline

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Pharmacology

Cite this

Influence of substituted tetrahydroisoquinolines and catecholamines on lipolysis, in vitro-II. Stereoselectivity. / Shonk, R. F.; Miller, Duane; Feller, D. R.

In: Biochemical Pharmacology, Vol. 20, No. 12, 01.01.1971, p. 3403-3412.

Research output: Contribution to journalArticle

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