Novel sites for phenylalkylamines: characterisation of a sodium-sensitive drug receptor with (-)-[3H]emopamil.
(-)-Emopamil ((S)-emopamil, (2S)-2-isopropyl-5-(methylphenethylamino)- 2-phenylvaleronitrile hydrochloride) is a Ca(2+)-antagonistic phenylalkylamine which also blocks serotonin (5-HT2) receptors and has antiischemic properties. The (-)-[3H]emopamil tissue distribution profile of specific binding is in striking contrast to that observed for (+)-[3H]PN 200-110 or (-)-[3H]desmethoxyverapamil: (-)-[3H]emopamil labels membrane fractions from guinea-pig liver much greater than adrenal gland greater than kidney approximately lung approximately ductus deferens approximately brain approximately skeletal muscle. Binding to liver membrane was saturable (KD = 12.8 nM, Bmax = 35 pmol/mg of protein), stereoselective, reversible (K-1 = 0.22 min-1 at 25 degrees C) and inhibited by tetraethylammonium (IC50: 1.8 mM) greater than Li+ (IC50: 12.5 mM) approximately Na+ (IC50: 13.6 mM) and [NH4+] (IC50: 79.3 mM) but not by Rb+, Cs+ or K+. The high-affinity liver membrane binding sites have a pharmacological profile that is distinct from the phenylalkylamine receptor domain of the voltage-dependent L-type Ca2+ channel. Similar sites exist in brain and other tissues, albeit with a lower density. Amiodarone, butoprozine and amiloride derivatives bind with high affinity whereas 1,4-dihydropyridines do not interact at all. It is suggested that the novel phenylalkylamine site is linked to a sodium-dependent carrier or transport system.
Zech
C
C
Institut für Biochemische Pharmakologie, Innsbruck, Austria.
Staudinger
R
R
Mühlbacher
J
J
Glossmann
H
H
D000818:Animals; D001665:Binding Sites; D002412:Cations / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism / Q000648:ultrastructure; D004095:Dihydropyridines / Q000378:metabolism; D006168:Guinea Pigs; D008099:Liver / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D011955:Receptors, Drug / Q000378:metabolism*; D014018:Tissue Distribution; D014316:Tritium; D014700:Verapamil / Q000031:analogs & derivatives* / Q000378:metabolism
D002412:Cations; D004095:Dihydropyridines; D011955:Receptors, Drug; D014316:Tritium; C043184:4-desmethoxyverapamil; D014700:Verapamil; C052752:emopamil