The Alkaloid Conessine And Analogues As Potent Histamine H-3 Receptor Antagonists

The naturally occurring alkaloid, conessine (6), was discovered to bind to histamine H-3 receptors in a radioligand-based high-throughput screen. Conessine displayed high affinity at both rat and human H-3 receptors (pK(i) = 7.61 and 8.27) and generally high selectivity against other sites, including histamine receptors H-1, H-2, and H-4. Conessine was found to efficiently penetrate the CNS and reach very high brain concentrations. Although the very slow CNS clearance and strong binding to adrenergic receptors discouraged focus on conessine itself for further development, its potency and novel steroid-based skeleton motivated further chemical investigation. Modification based on introducing diversity at the 3-nitrogen position generated a new series of H-3 antagonists with higher in vitro potency, improved target selectivity, and more favorable drug-like properties. One optimized analogue (13c) was examined in detail and was found to be efficacious in animal behavioral model of cognition.