Activation of adenylate cyclase and inhibition of glucose transport in rat adipocytes by forskolin analogues: Structural determinants for distinct sites of action

H. G. Joost, A. D. Habberfield, Ian Simpson, A. Laurenza, K. B. Seamon

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Abstract

Forskolin and four analogues of forskolin, 7-β-[γ-(N'-methylpiperazino)-butyryloxy]-7-desacetylforskolin, 7-desacetylforskolin 7-toxyl-7-desacetylforskolin, and 1,9-dideoxyforskolin, were tested for their ability to activate adenylate cyclase, inhibit glucose transport, and inhibit cytochalasin B binding in rat adipocyte membranes. Forskolin was the most potent analogue in activating adenylate cyclase with an EC50 of 2 μM, whereas 7-β-[γ-(N'-methylpiperazino)butyryloxy]-7-desacetylforskolin and 7-desacetylforskolin were less potent, with EC50 values of 3 μM and 20 μM, respectively. The 7-tosyl-7-desacetylforskolin and 1,9-dideoxyforskolin did not stimulate adenylate cyclase even at the highest concentrations tested (100 μM). In contrast, forskolin and all of the analogues were able to fully inhibit glucose transport in adipocyte plasma membranes. The order of potency for the inhibition was forskolin > 7-β-[γ-(N'-methylpiperazino)butyryloxy]-7-desacetylforskolin > 7-desacetylforskolin > 7-tosyl-7-desacetylforskolin > 1,9-dideoxyforskolin, and the EC50 values were 0.24 μM, 1.8 μM, 7.1 μM 8.8 μM, and 12.8 μM, respectively. Cytochalasin B binding to rat adipocyte membranes was inhibited by forskolin and the four analogues with the same order of potency as observed for the inhibition of glucose transport. Thus, the site of action of forskolin which is responsible for the inhibition of glucose transport and cytochasin B binding exhibits structural requirements for forskolin and its analogues that are different from those of the site responsible for the activation of adenylate cyclase.

Original languageEnglish (US)
Pages (from-to)449-453
Number of pages5
JournalMolecular pharmacology
Volume33
Issue number4
StatePublished - Jan 1 1988

Fingerprint

Colforsin
Adenylyl Cyclases
Adipocytes
Glucose
Cytochalasin B
Membranes
7-desacetylforskolin
Cell Membrane
1,9-dideoxyforskolin

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

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title = "Activation of adenylate cyclase and inhibition of glucose transport in rat adipocytes by forskolin analogues: Structural determinants for distinct sites of action",
abstract = "Forskolin and four analogues of forskolin, 7-β-[γ-(N'-methylpiperazino)-butyryloxy]-7-desacetylforskolin, 7-desacetylforskolin 7-toxyl-7-desacetylforskolin, and 1,9-dideoxyforskolin, were tested for their ability to activate adenylate cyclase, inhibit glucose transport, and inhibit cytochalasin B binding in rat adipocyte membranes. Forskolin was the most potent analogue in activating adenylate cyclase with an EC50 of 2 μM, whereas 7-β-[γ-(N'-methylpiperazino)butyryloxy]-7-desacetylforskolin and 7-desacetylforskolin were less potent, with EC50 values of 3 μM and 20 μM, respectively. The 7-tosyl-7-desacetylforskolin and 1,9-dideoxyforskolin did not stimulate adenylate cyclase even at the highest concentrations tested (100 μM). In contrast, forskolin and all of the analogues were able to fully inhibit glucose transport in adipocyte plasma membranes. The order of potency for the inhibition was forskolin > 7-β-[γ-(N'-methylpiperazino)butyryloxy]-7-desacetylforskolin > 7-desacetylforskolin > 7-tosyl-7-desacetylforskolin > 1,9-dideoxyforskolin, and the EC50 values were 0.24 μM, 1.8 μM, 7.1 μM 8.8 μM, and 12.8 μM, respectively. Cytochalasin B binding to rat adipocyte membranes was inhibited by forskolin and the four analogues with the same order of potency as observed for the inhibition of glucose transport. Thus, the site of action of forskolin which is responsible for the inhibition of glucose transport and cytochasin B binding exhibits structural requirements for forskolin and its analogues that are different from those of the site responsible for the activation of adenylate cyclase.",
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Activation of adenylate cyclase and inhibition of glucose transport in rat adipocytes by forskolin analogues : Structural determinants for distinct sites of action. / Joost, H. G.; Habberfield, A. D.; Simpson, Ian; Laurenza, A.; Seamon, K. B.

In: Molecular pharmacology, Vol. 33, No. 4, 01.01.1988, p. 449-453.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Activation of adenylate cyclase and inhibition of glucose transport in rat adipocytes by forskolin analogues

T2 - Structural determinants for distinct sites of action

AU - Joost, H. G.

AU - Habberfield, A. D.

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AU - Laurenza, A.

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N2 - Forskolin and four analogues of forskolin, 7-β-[γ-(N'-methylpiperazino)-butyryloxy]-7-desacetylforskolin, 7-desacetylforskolin 7-toxyl-7-desacetylforskolin, and 1,9-dideoxyforskolin, were tested for their ability to activate adenylate cyclase, inhibit glucose transport, and inhibit cytochalasin B binding in rat adipocyte membranes. Forskolin was the most potent analogue in activating adenylate cyclase with an EC50 of 2 μM, whereas 7-β-[γ-(N'-methylpiperazino)butyryloxy]-7-desacetylforskolin and 7-desacetylforskolin were less potent, with EC50 values of 3 μM and 20 μM, respectively. The 7-tosyl-7-desacetylforskolin and 1,9-dideoxyforskolin did not stimulate adenylate cyclase even at the highest concentrations tested (100 μM). In contrast, forskolin and all of the analogues were able to fully inhibit glucose transport in adipocyte plasma membranes. The order of potency for the inhibition was forskolin > 7-β-[γ-(N'-methylpiperazino)butyryloxy]-7-desacetylforskolin > 7-desacetylforskolin > 7-tosyl-7-desacetylforskolin > 1,9-dideoxyforskolin, and the EC50 values were 0.24 μM, 1.8 μM, 7.1 μM 8.8 μM, and 12.8 μM, respectively. Cytochalasin B binding to rat adipocyte membranes was inhibited by forskolin and the four analogues with the same order of potency as observed for the inhibition of glucose transport. Thus, the site of action of forskolin which is responsible for the inhibition of glucose transport and cytochasin B binding exhibits structural requirements for forskolin and its analogues that are different from those of the site responsible for the activation of adenylate cyclase.

AB - Forskolin and four analogues of forskolin, 7-β-[γ-(N'-methylpiperazino)-butyryloxy]-7-desacetylforskolin, 7-desacetylforskolin 7-toxyl-7-desacetylforskolin, and 1,9-dideoxyforskolin, were tested for their ability to activate adenylate cyclase, inhibit glucose transport, and inhibit cytochalasin B binding in rat adipocyte membranes. Forskolin was the most potent analogue in activating adenylate cyclase with an EC50 of 2 μM, whereas 7-β-[γ-(N'-methylpiperazino)butyryloxy]-7-desacetylforskolin and 7-desacetylforskolin were less potent, with EC50 values of 3 μM and 20 μM, respectively. The 7-tosyl-7-desacetylforskolin and 1,9-dideoxyforskolin did not stimulate adenylate cyclase even at the highest concentrations tested (100 μM). In contrast, forskolin and all of the analogues were able to fully inhibit glucose transport in adipocyte plasma membranes. The order of potency for the inhibition was forskolin > 7-β-[γ-(N'-methylpiperazino)butyryloxy]-7-desacetylforskolin > 7-desacetylforskolin > 7-tosyl-7-desacetylforskolin > 1,9-dideoxyforskolin, and the EC50 values were 0.24 μM, 1.8 μM, 7.1 μM 8.8 μM, and 12.8 μM, respectively. Cytochalasin B binding to rat adipocyte membranes was inhibited by forskolin and the four analogues with the same order of potency as observed for the inhibition of glucose transport. Thus, the site of action of forskolin which is responsible for the inhibition of glucose transport and cytochasin B binding exhibits structural requirements for forskolin and its analogues that are different from those of the site responsible for the activation of adenylate cyclase.

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