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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.

1 Experiments have been performed in order to analyse the mechanism whereby SCA40, a new imidazo[1,2-a]pyrazine derivative relaxes airway smooth muscle.2 SCA40 (0.01-10 gM) caused a complete and concentration-dependent relaxation of guinea-pig isolated trachea contracted with 20 mM KC1 but failed to inhibit completely the spasmogenic effects of 80mM KC1.3 Quinine (30 gM) antagonized the relaxant activity of SCA40 in 20 mM KCl-contracted guinea-pig isolated trachea. The ATP-sensitive K+-channel blocker, glibenclamide (3 gM), did not antagonize the relaxant activity of SCA40 in either 20 mM KC1 or 1 JLM carbachol-contracted isolated trachea. 4 SCA40 (0.01-10tM) and isoprenaline (0.1 nM-10 M) caused a complete and concentrationdependent relaxation of guinea-pig isolated trachea contracted with carbachol 1 ELM. 5 The large-conductance Ca2+-activated K+-channel blocker, charybdotoxin (60-180 nM), non-competitively antagonized the relaxant activity of isoprenaline on 1 gM carbachol-contracted trachea. The inhibition was characterized by rightward shifts of the isoprenaline concentration-relaxation curves with depression of their maxima. 6 The relaxant activity of SCA40 in 1 gM carbachol-contracted trachea was antagonized by charybdotoxin (60-600 nM) in an apparently competitive manner. The concentration-relaxation curves to SCA40 were shifted to the right with no significant alteration in the maximum response. 7 It is concluded that SCA40 is a novel potassium channel opener which is a potent relaxant of guinea-pig airway smooth muscle in vitro. The relaxant activity of SCA40 does not involve ATPsensitive K+-channels but rather large-conductance Ca2'-activated K+-channels or other charybdotoxinsensitive K+-channels.