Profile of the oppositely acting enantiomers of the dihydropyridine 202–791 in cardiac preparations: Receptor binding, electrophysiological, and pharmacological studies

Williams, Judith S.; Grupp, Ingrid L.; Grupp, Günter; Vághy, Pál L.; Dumont, Louis; Schwartz, Arnold; Yatani, Atsuko; Hamilton, Susan L.; Brown, Arthur M.

doi:10.1016/0006-291x(85)91763-2

Cited by 69 publications

(35 citation statements)

References 13 publications

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“…One receptor specifically binds, 1,4-dihydropyridine derivatives with dissociation constants in the pM-nM range (Glossmann et al, 1982;Bolger et al, 1983;Fosset et al, 1983;Janis et al, 1984b;. Present evidence suggests that a single dihydropyridine receptor is responsible for binding both Ca channel activating and inhibiting dihydropyridines Williams et al, 1985;Kokubun et al, 1986;Hamilton et al, 1987;Maan & Hosey, 1987). However, some recent data Brown, Kunze & Yatani, 1986) suggests that there may be more than one high affinity binding site associated with the dihydropyridine receptor, one associated with activation of the channel and the other with inhibition (see below).…”

Section: Multiple Drug Receptors Are Present On L-type Ca Channels Anmentioning

confidence: 78%

Calcium channels: Molecular pharmacology, structure and regulation

1988

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Section: Multiple Drug Receptors Are Present On L-type Ca Channels Anmentioning

confidence: 78%

Calcium channels: Molecular pharmacology, structure and regulation

1988

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“…As can be seen in fig.3 (-)(R)-202-791 stimulated whereas ( +)(S)-202-791 was inhibitory. The (R) enantiomer is a potent Ca 2+-channel blocker whereas the (5') enantiomer is a potent agonist [19]. Likewise (+)(4R)-Bay K 8644 (a channel blocker) stimulated (EC50 = 100 t 58 nM, maximal stimulation = 33 -t 9%) whereas ( -)(4S)-Bay K 8644, a channel agonist 1201, was inhibitory (not shown).…”

Section: 3 Binding Assaysmentioning

confidence: 99%

Purified calcium channels have three allosterically coupled drug receptors

Striessnig¹,

Göll²,

Moosburger³

et al. 1986

FEBS Letters

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(−)‐[3H]Desmethoxyverapamil and (+)‐[3P]PN 200‐110 were employed to characterize phenylalkylamineselective and 1,4‐dihydropyridine‐selective receptors on purified Ca2+ channels from guinea‐pig skeletal muscle t‐tubules. In contrast to the membrane‐bound Ca2+ channel, d‐cis‐diltiazem (EC50 = 4.5 ± 1.7 μM) markedly stimulated the binding of (+)‐[3H]PN 200‐110 to the purified ionic pore. In the presence of 100 μM d‐cis‐diltiazem (which binds to the benzothiazepine‐selective receptors) the B max for (+)‐[3H]PN 200‐110 increased from 497 ± 81 to 1557 ± 43 pmol per mg protein, whereas the K d decreased from 8.8 ± 1.7 to 4.7 ± 1.8 nM at 25°C. P‐cis‐Diltiazem was inactive. (−)‐Desmethoxyverapamil, which is a negative heterotropic allosteric inhibitor of (+)‐[3H]IN 200‐110 binding to membrane‐bound channels, stimulated 1,4‐dihydropyridine binding to the isolated channel. (−)‐[3H]Desmethoxyverapamil binding was stimulated by antagonistic 1,4‐dihydropyridines [(+)‐PN 200‐110 ⪢(−)(CR)‐202‐791 ⪢(+)(4R)‐Bay K 8644] whereas the agonistic enantiomers (+)(S)‐202‐791 and (−)(4S)‐Bay K 8644 were inhibitory and (−)‐PN 200‐110 was inactive. The results indicate that three distinct drug‐receptor sites exist on the purified Ca2+ channel, two of which are shown by direct labelling to be reciprocally allosterically coupled.

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“…The DHP antagonist (-)-S202-791 reduced Ba2+ currents at all potentials between -10 and +60 mV. The block appeared to be greater on the more slowly inactivating component compared to the peak current (20) and depended upon the holding potential (Fig. 6 A-C).…”

Section: Resultsmentioning

confidence: 96%

Cloning, chromosomal localization, and functional expression of the alpha 1 subunit of the L-type voltage-dependent calcium channel from normal human heart.

Schultz

Mikala

Yatani

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

118

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A unique structural variant of the cardiac L-type voltage-dependent calcium channel a, subunit cDNA was isolated from libraries derived from normal human heart mRNA. The deduced amino acid sequence shows significant homology to other calcium channel a, subunits. However, differences from the rabbit heart a, include a shortened N-terminus, a unique C-terminal insertion, and both forms of an alternatively spliced motif IV S3 region. The shortened N-terminus provides optimal access to consensus sequences thought to facilitate translation. Northern blot analysis revealed a single hybridizing mRNA species of 9.4 kb. The gene for the human heart a, subunit was localized specifically to the distal region of chromosome 12pl3. The cloned a, subunit was expressed in Xenopus oocytes and single-channel analyses revealed native-like pharmacology and channel properties.

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Profile of the oppositely acting enantiomers of the dihydropyridine 202–791 in cardiac preparations: Receptor binding, electrophysiological, and pharmacological studies

Cited by 69 publications

References 13 publications

Calcium channels: Molecular pharmacology, structure and regulation

Calcium channels: Molecular pharmacology, structure and regulation

Purified calcium channels have three allosterically coupled drug receptors

Cloning, chromosomal localization, and functional expression of the alpha 1 subunit of the L-type voltage-dependent calcium channel from normal human heart.

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