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Very high affinity interaction of DPI 201‐106 and BDF 8784 enantiomers with the phenylalkylamine‐sensitive Ca 2+ ‐channel in Drosophila head membranes
Author(s) -
Glossmann Hartmut,
Zech Christina,
Striessnig Jörg,
Staudinger Robert,
Hall Linda,
Greenberg Robert,
Armah Benjamin I.
Publication year - 1991
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1991.tb12193.x
Subject(s) - chemistry , enantiomer , stereochemistry , biophysics , pharmacology , biology
1 Piperazinylindoles (DPI 201‐106, BDF 8784), drugs known to act on voltage‐dependent Na + ‐channels, bind with very high affinity to a Ca 2+ ‐channel‐associated phenylalkylamine receptor in Drosophila melanogaster head membranes. These compounds and (+)‐tetrandrine, a naturally occurring Ca 2+ ‐antagonist, were the most selective inhibitors for phenylalkylamine‐labelled Drosophila Ca 2+ ‐channels compared to mammalian L‐type Ca 2+ ‐channels. 2 Replacement of the cyano group by a methyl group in (+)‐DPI 201‐106 ((+)‐BDF 8784) increases the IC 50 value for inhibition of phenylalkylamine labelling of Drosophila Ca 2+ ‐channels from 0.29 to 2.1 n m but decreases the IC 50 value for inhibition of phenylalkylamine labelling of mammalian skeletal muscle Ca 2+ ‐channels from 3480 to 49 n m . 3 DPI 201‐106 enantiomers completely block (at 0.1 μ m ) phenylalkylamine photolabelling of a 136 K polypeptide in Drosophila head membranes whereas 10 μ m aconitine or lidocaine are without effect. 4 Assessment of the Ca 2+ ‐antagonist effects of the substituted DPI 201‐106 enantiomers in K + ‐depolarized taenia strips from guinea‐pig caecum yielded pA 2 values of 6.33 ± 0.07 for (−)‐BDF 8784 and 6.99 ± 0.17 for (+)‐BDF 8784, respectively. 5 Piperazinylindoles, previously believed to act nonspecifically on voltage‐dependent mammalian L‐type Ca 2+ ‐channels, therefore have stereoselectivity for a novel binding site and chemical selectivity unrelated to local anaesthetic activity. 6 It is proposed that a very high affinity piperazinylindole‐selective site is coupled to the phenylalkylamine receptor of Drosophila Ca 2+ ‐channels. These sites are still present on mammalian L‐type Ca 2+ ‐channels but have lower affinity and/or are less tightly coupled to phenylalkylamine receptors on the α 1 ‐subunit.