Frequency-dependent inhibition of neurotransmitter release by besipirdine and HP 184.
We have described the interaction of besipirdine (HP 749, N-(n-propyl)-N-(4-pyridinyl)-1H-indol-1-amine hydrochloride) with voltage-dependent Na+ channels (Tang et al., 1995, Br. J. Pharmacol. 116,2468). Here we describe studies with besipirdine and a related compound, HP 184 (N-(n-propyl)-3-fluoro-4-pyridinyl)-1H-3-methylindol-1-amine hydrochloride), showing that this interaction is voltage-dependent and leads to frequency-dependent inhibition of electrically stimulated neurotransmitter release. Thus, the inhibition of veratridine-induced increases in intracellular Ca2+ was enhanced by depolarization with KCl (IC50 shifted from 23.8 +/- 1.4 microM in 5 mM KCl to 7.3 +/- 1.2 microM in 15 mM KCl for besipirdine and from 58.2 +/- 1.3 microM for HP 184). Moreover, the enhancement of electrically stimulated [3H]norepinephrine release by besipirdine was diminished at higher frequencies of stimulation. As has been previously suggested for such compounds, we predict that besipirdine would act as a filter in the brain allowing signalling at low frequencies but blocking transmission at high frequencies.
Tang
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L
Neuroscience Therapeutic Domain, Hoechst Marion Roussel, Sommerville, NJ 08876, USA.
Kongsamut
S
S
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004558:Electric Stimulation; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D010276:Parasympatholytics / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015222:Sodium Channels / Q000187:drug effects; D013574:Synaptosomes / Q000187:drug effects* / Q000378:metabolism; D014701:Veratridine / Q000037:antagonists & inhibitors*
D007211:Indoles; D010276:Parasympatholytics; D011725:Pyridines; D015222:Sodium Channels; D014701:Veratridine; C074872:besipirdine; C101289:nerispirdine; D002118:Calcium; D009638:Norepinephrine