Adamantane derivatives: a new class of insulin secretagogues

Abstract

1 Adamantane derivatives were found to increase insulin release in vitro. Mouse islets were used to study the mechanisms and molecular requirements of that hitherto unrecognised property.2 At a non-stimulatory concentration of glucose (3mM), 1-adamantanamine (1 mM) reversibly inhibited`6Rb efflux from islet cells, depolarized the P-cell membrane, induced electrical activity, stimulated 45Ca uptake and efflux, and triggered insulin release. Omission of extracellular Ca2" abolished the secretory response but only partially inhibited the acceleration of 45Ca efflux.3 At a stimulatory concentration of glucose (10 mM), 1-adamantanamine reversibly increased '8Rb efflux, potentiated electrical activity (lengthening of the slow waves with spikes), augmented 45Ca uptake and efflux, and increased insulin release. The effects of adamantanamine were dose-dependent, with a threshold concentration of 1O iM for stimulation of release. 4 2-Adamantanamine was as potent as l-adamantanamine. In contrast, substitution of the amino group by a carboxyl group (l-adamantanecarboxylic acid) decreased the effectiveness by about 65%, and substitution by a hydroxyl group (1-adamantanol) suppressed it.

Amantadine and sparteine inhibit ATP‐regulated K‐currents in the insulin‐secreting β‐cell line, HIT‐T15

“…This hypothesis is supported by the observation that sparteine antagonizes the increase in 86Rb efflux induced by diazoxide (Paolisso et al, 1985), an activator of K-ATP channels (Trube et al, 1986). Although a quantitative comparison is difficult, owing to the difference in experimental protocols, the concentrations reported for stimulation of insulin secretion by amantadine and sparteine (Paolisso et al, 1985;Garrino & Henquin, 1987) are compatible with the Ki's we obtained for K-ATP channel inhibition.…”

“…Both these drugs have been shown to reduce the resting membrane Kpermeability of fl-cells and thereby elicit insulin release in the presence of non-stimulatory levels of glucose (Paolisso et al, 1985;Garrino & Henquin, 1987). It seems probable that these effects of sparteine and amantadine result from their ability to inhibit K-ATP channels, since K-ATP channel activity principally accounts for the resting K-permeability of the fl-cell (Ashcroft et al, 1988).…”

“…Recently, several other moieties, unrelated to the sulphonylureas, have been found to stimulate insulin release from isolated islets in the absence of glucose, whilst concomitantly reducing resting membrane K+ permeability (Henquin, 1990). Among these are the tricyclic compound, 1-adamantanamine (amantadine) (Garrino & Henquin, 1987) and the alkaloid sparteine (Paolisso et al, 1985). It seems probable that the effect of these compounds on insulin release is also mediated via inhibition of the K-ATP channel, since this channel contributes most of the resting K-permeability of the fl-cell (Ashcroft et al, 1988).…”

“…It seems probable that the effect of these compounds on insulin release is also mediated via inhibition of the K-ATP channel, since this channel contributes most of the resting K-permeability of the fl-cell (Ashcroft et al, 1988). Amantadine is of special interest since substitution of its amine group alters its efficacy as an insulin secretagogue; thus, carboxyl substitution (1-adamantanecarboxylic acid) reduces its potency, whilst hydroxyl substitution (1-adamantanol) renders it ineffective (Garrino & Henquin, 1987). Clinically, amantadine is used in parkinsonism and as a viral prophylactic (Parkes, 1974) although its mode of action is unknown.…”

Simultaneous liquid chromatographic assay of amantadine and its four related compounds in phosphate-buffered saline using 4-fluoro-7-nitro-2,1,3-benzoxadiazole as a fluorescent derivatization reagent

“…2-Adamantanamine hydrochloride (2-ADA) has been found to be a possible drug candidate for a new class of insulin secretagogues in in vitro experiments (Garrino and Henquin, 1987), although it is not recognized as an agent for Parkinson's disease. 1-(1-Adamantyl)ethylamine hydrochloride (rimantadine, RIM) exhibits equal efficacy and fewer adverse reactions than AMA, and it has been reported to be effective against influenza (Wingfield et al, 1969;Dolin et al, 1982).…”