title: Very high affinity interaction of DPI 201-106 and BDF 8784 enantiomers with the phenylalkylamine-sensitive Ca2(+)-channel in Drosophila head membranes.
abstract: 1. Piperazinylindoles (DPI 201-106, BDF 8784), drugs known to act on voltage-dependent Na(+)-channels, bind with very high affinity to a Ca2(+)-channel-associated phenylalkylamine receptor in Drosophila melanogaster head membranes. These compounds and (+)-tetrandrine, a naturally occurring Ca2(+)-antagonist, were the most selective inhibitors for phenylalkylamine-labelled Drosophila Ca2(+)-channels compared to mammalian L-type Ca2(+)-channels. 2. Replacement of the cyano group by a methyl group in (+)-DPI 201-106 ((+)-BDF 8784) increases the IC50 value for inhibition of phenylalkylamine labelling of Drosophila Ca2(+)-channels from 0.29 to 2.1 nM but decreases the IC50 value for inhibition of phenylalkylamine labelling of mammalian skeletal muscle Ca2(+)-channels from 3480 to 49 nM. 3. DPI 201-106 enantiomers completely block (at 0.1 microM) phenylalkylamine photolabelling of a 136 K polypeptide in Drosophila head membranes whereas 10 microM aconitine or lidocaine are without effect. 4. Assessment of the Ca2(+)-antagonist effects of the substituted DPI 201-106 enantiomers in K(+)-depolarized taenia strips from guinea-pig caecum yielded pA2 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 Ca2(+)-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 Ca2(+)-channels. These sites are still present on mammalian L-type Ca2(+)-channels but have lower affinity and/or are less tightly coupled to phenylalkylamine receptors on the alpha 1-subunit.
authors.affiliation: Institut für Biochemische Pharmakologie, Innsbruck, Austria.
authors.forename: H
authors.initials: H
authors.lastname: Glossmann
authors.forename: C
authors.initials: C
authors.lastname: Zech
authors.forename: J
authors.initials: J
authors.lastname: Striessnig
authors.forename: R
authors.initials: R
authors.lastname: Staudinger
authors.forename: L
authors.initials: L
authors.lastname: Hall
authors.forename: R
authors.initials: R
authors.lastname: Greenberg
authors.forename: B I
authors.initials: BI
authors.lastname: Armah
mesh_terms: D000345:Affinity Labels; D000818:Animals; D001665:Binding Sites; D015220:Calcium Channels / Q000378:metabolism*; D004331:Drosophila melanogaster; D007211:Indoles / Q000378:metabolism*; D010879:Piperazines / Q000378:metabolism*; D011978:Receptors, Nicotinic / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D000345:Affinity Labels; D015220:Calcium Channels; D007211:Indoles; D010879:Piperazines; D011978:Receptors, Nicotinic; D015222:Sodium Channels; C060322:BDF 8784; C046261:DPI 201-106