Activation of L-type calcium channel by tolazoline derivatives

Role of isothiocyanate moiety

Longping Lei, Pal L. Vaghy, Meri Slavica, J. De Los Angeles, Brent Smith, Duane Miller, Dennis R. Feller

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Studies have investigated the pharmacologic mechanism of 2-(4'- isothiocyanatobenzyl) imidazoline (IBI) and analogs for interaction with imidazoline receptors (IRs), α-adrenergic receptors (α-ARs), and calcium channels in cardiovascular muscle systems. IBI differs from tolazoline by substitution of an electrophilic isothiocyanato (NCS) group. Unlike tolazoline, which is a partial α-AR agonist, IBI produced an irreversible, slow-onset, and sustained contraction of rat aorta with an median effective concentration (EC50) value of 5 μM, and a maximal contraction (116%) greater than that of phenylephrine (100%) and tolazoline (59%). The IBI- induced contractions were dependent on calcium channels and independent of α-ARs or IRs. Similarly, structure-activity relation studies in rat aortic smooth muscles on a series of synthesized IBI analogs indicated that NCS analogs, but not those without the NCS group, exhibited effects by a non-α- AR, non-IR, but a calcium channel-dependent mechanism. Thus the presence of an intact IBI ring in these analogs is not a requirement for these activities. Further, IBI inhibited dihydropyridine (DHP, [3H]PN 200-110 and [3H]Bay K 8644) binding to L-type calcium channels of T-tubule membranes in rabbit skeletal muscle. In contrast to nifedipine, IBI and NCS derivatives (nifedipine-NCS, naphazoline-NCS) only partially (50-88%) displaced specific binding of these radioligands. A single site of noncooperative interaction was observed for nifedipine (n(H) = 0.97), whereas tolazoline-NCS (IBI, n(H) = 1.46) and nifedipine-NCS (n(H) = 1.37) exhibited a positive cooperativity in binding to DHP sites. These receptor-binding data indicate that NCS derivatives bind to L-type calcium channels and interact allosterically with DHP-binding sites. Direct binding of the NCS group to specific nucleophilic protein sites of the calcium channel may be responsible for its activation and the subsequent contractile effects of IBI.

Original languageEnglish (US)
Pages (from-to)721-733
Number of pages13
JournalJournal of Cardiovascular Pharmacology
Volume31
Issue number5
DOIs
StatePublished - May 1 1998

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Tolazoline
L-Type Calcium Channels
Calcium Channels
Nifedipine
Imidazoline Receptors
2-(4'-isothiocyanatobenzyl)imidazoline
isothiocyanic acid
Isradipine
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester
Naphazoline
Phenylephrine
Cardiovascular System
Adrenergic Receptors
Smooth Muscle
Aorta
Skeletal Muscle
Binding Sites

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

Activation of L-type calcium channel by tolazoline derivatives : Role of isothiocyanate moiety. / Lei, Longping; Vaghy, Pal L.; Slavica, Meri; De Los Angeles, J.; Smith, Brent; Miller, Duane; Feller, Dennis R.

In: Journal of Cardiovascular Pharmacology, Vol. 31, No. 5, 01.05.1998, p. 721-733.

Research output: Contribution to journalArticle

Lei, Longping ; Vaghy, Pal L. ; Slavica, Meri ; De Los Angeles, J. ; Smith, Brent ; Miller, Duane ; Feller, Dennis R. / Activation of L-type calcium channel by tolazoline derivatives : Role of isothiocyanate moiety. In: Journal of Cardiovascular Pharmacology. 1998 ; Vol. 31, No. 5. pp. 721-733.
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