Rigid Analogues of the α2-Adrenergic Blocker Atipamezole: Small Changes, Big Consequences

We report the discovery of a new family of alpha(2) adrenergic receptor antagonists derived from atipamezole. Affinities of the compounds at human alpha(2) in alpha(1h) receptors as well as their functional activities at h alpha(2A) receptors were determined in competition binding and G-protein activation assays, respectively. Central antagonist activities were confirmed in mice alter oral administration. Further studies on a selected example: (+)-4-(1a,6-dihydro-1 H-cyclopropa]inden-6a-yl)-1H-imidazole, (+)-1 (F 148055), were undertaken to probe the potential of the series. On the one hand, (+)-1 increased the release of noradrenaline in mouse frontal cortex following acute systemic administration, the magnitude of this effect being much larger than that obtained with reference agents. On the other, (+1)-1 produced minimal cardiovascular effects in intact, anesthetized rat, a surprising outcome that might be explained by its differential action at peripheral and central alpha(2) receptors. A strategy for improving the therapeutic window of alpha(2) antagonists is put forward.