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

Abstract

We report the discovery of a new family of α(2) adrenergic receptor antagonists derived from atipamezole. Affinities of the compounds at human α(2) and α(1b) receptors as well as their functional activities at hα(2A) receptors were determined in competition binding and G-protein activation assays, respectively. Central α(2) antagonist activities were confirmed in mice after oral administration. Further studies on a selected example: (+)-4-(1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazole, (+)-1 (F 14805), 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 produced minimal cardiovascular effects in intact, anesthetized rat, a surprising outcome that might be explained by its differential action at peripheral and central α(2) receptors. A strategy for improving the therapeutic window of α(2) antagonists is put forward.

Comprehensive Review in Current Developments of Imidazole-Based Medicinal Chemistry

“…It could effectively trigger the release of cortical noradrenaline in mouse after acute systemic administration, which was 30‐fold more potent than fipamezole and atipamezole. Interestingly, it could substantially increase the blood pressure in pithed rat but exert minimal cardiovascular effect in intact and anesthetized rat, suggesting its opposed central and peripheral actions …”

New and unusual scaffolds in medicinal chemistry

“…9), a potent antagonist of presynaptic a 2A C À1 receptors; however, it also stimulated vascular a 2 receptors, leading to substantial increase in blood pressure in the pithed rat. 29 The (+)-enantiomer of 18 is a potent partial agonist of GPR109a and reduces fatty acid levels in human adipocytes and mice. 30…”

Synthesis of Trifluoromethyl‐Substituted 3‐Azabicyclo[n.1.0]alkanes: Advanced Building Blocks for Drug Discovery

“…For example, Vacher and colleagues recently showed that cyclopropane‐containing compound 18 exhibited an affinity of two orders of magnitude higher to the α‐adrenergic receptor relative to the known drug Atipamezole (Figure 6). 25 In this context, the synthesized amines are the ideal candidates for the diversity‐oriented conformational‐restriction strategy 24e…”