Synthesis and antibronchospastic activity of 8-alkoxy- and 8-(alkylamino)imidazo[1,2-a]pyrazines

Abstract

Theophylline still occupies a dominant place in asthma therapy. Unfortunately its adverse central nervous system (CNS) stimulant effects can dramatically limit its use, and adjustments in the dosage are often needed. We have synthesized a new series of imidazo[1,2-alpha]pyrazine derivatives which are much more potent bronchodilators than theophylline in vivo and do not exhibit the CNS stimulatory profile. In vitro studies on isolated rat uterus and guinea pig trachea confirm the high potentialities of these derivatives. 6-Bromo-8-(methylamino)imidazo[1,2-alpha]-pyrazine-3-carbonitrile (23) is identified as the most potent compound of the series. As in the case of theophylline, phosphodiesterase inhibition appears unlikely to be the unique mechanism of action of this series of heterocycles.

Further analysis of the mechanisms underlying the tracheal relaxant action of SCA40

“…We conclude that the suggestion of Laurent et al (1992) that SCA40 (<10 JLM) relaxes guinea-pig trachea by opening BKc channels is unlikely to be correct. As discussed below, this agent is more likely to promote tracheal relaxation by virtue of its activity as an inhibitor of cyclic AMP-PDE. Role of cyclic nucleotide phosphodiesterase inhibition in the tracheal relaxant action of SCA40…”

“…Using an enzyme preparation derived from bovine heart (Sigma P0134), Bonnet et al (1992) ; present study). However, in guinea-pig trachea, the cyclic AMP hydrolysing isoenzyme that mainly regulates mechanical tone is the type III isoenzyme with the type IV isoenzyme perhaps playing a supportive role (Harris et al, 1989;Berry et al, 1991).…”

Cardiovascular effects of SCA40, a novel potassium channel opener, in rats

“…The substances used were obtained from the following sources: SCA40 was synthesized as already described (Bonnet et al, 1992 The Chenoweth-Koelle solution used in the tissue bath experiments had the following composition (mM): NaCl 120, KCI 5.6, CaCl2 2.4, MgCl2 2.2, NaHCO3 15 and glucose 10. This solution was maintained at 37°C and gassed continuously with a mixture of 95% 02, 5% CO2.…”

“…Its weak cyclic AMP phosphodiesterase inhibitory activity only partially explains these relaxant properties (Bonnet et al, 1992). Since SCA40 failed to inhibit completely the spasmogenic effects of 80 mM KCI in guineapig isolated trachealis, potassium channel opening properties have been proposed for it (Laurent et al, 1993).…”

A comparison of the effects of SCA40, NS 004 and NS 1619 on large conductance Ca2+‐activated K+ channels in bovine tracheal smooth muscle cells in culture

“…Recently, a series of imidazopyrazine derivatives have been synthesized which possess smooth muscle relaxant actions (Bonnet et al, 1992). The most potent of these compounds, SCA40, has been reported to exert its relaxant effects by opening BKca channels, a conclusion based on the sensitivity of the SCA40-induced relaxation to the BKca channel blocker, charybdotoxin (ChTX), and on the observation that the relaxation was attenuated when 80 mM KCl was used as the spasmogen (Laurent et al, 1993).…”