title: The alkaloid conessine and analogues as potent histamine H3 receptor antagonists.
abstract: The naturally occurring alkaloid, conessine (6), was discovered to bind to histamine H3 receptors in a radioligand-based high-throughput screen. Conessine displayed high affinity at both rat and human H3 receptors (pKi = 7.61 and 8.27) and generally high selectivity against other sites, including histamine receptors H1, H2, and H4. 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 H3 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.
authors.affiliation: Department of Neuroscience Research, Global Pharmaceutical Research Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6123, USA. chen.zhao@abbott.com
authors.forename: Chen
authors.initials: C
authors.lastname: Zhao
authors.forename: Minghua
authors.initials: M
authors.lastname: Sun
authors.forename: Youssef L
authors.initials: YL
authors.lastname: Bennani
authors.forename: Sujatha M
authors.initials: SM
authors.lastname: Gopalakrishnan
authors.forename: David G
authors.initials: DG
authors.lastname: Witte
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Miller
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Krueger
authors.forename: Kaitlin E
authors.initials: KE
authors.lastname: Browman
authors.forename: Christine
authors.initials: C
authors.lastname: Thiffault
authors.forename: Jill
authors.initials: J
authors.lastname: Wetter
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Hancock
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Esbenshade
authors.forename: Marlon D
authors.initials: MD
authors.lastname: Cowart
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D001923:Brain Chemistry; D003071:Cognition / Q000187:drug effects; D006633:Histamine Antagonists / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D011869:Radioligand Assay; D051381:Rats; D018100:Receptors, Histamine H3 / Q000187:drug effects*
chemical_list: D000470:Alkaloids; D006633:Histamine Antagonists; D018100:Receptors, Histamine H3; C007111:conessine