The alkaloid conessine and analogues as potent histamine H3 receptor antagonists.
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.
Zhao
Chen
C
Department of Neuroscience Research, Global Pharmaceutical Research Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064-6123, USA. chen.zhao@abbott.com
Sun
Minghua
M
Bennani
Youssef L
YL
Gopalakrishnan
Sujatha M
SM
Witte
David G
DG
Miller
Thomas R
TR
Krueger
Kathleen M
KM
Browman
Kaitlin E
KE
Thiffault
Christine
C
Wetter
Jill
J
Marsh
Kennan C
KC
Hancock
Arthur A
AA
Esbenshade
Timothy A
TA
Cowart
Marlon D
MD
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*
D000470:Alkaloids; D006633:Histamine Antagonists; D018100:Receptors, Histamine H3; C007111:conessine