Nudicauline and elatine as potent norditerpenoid ligands at rat neuronal alpha-bungarotoxin binding sites: importance of the 2-(methylsuccinimido)benzoyl moiety for neuronal nicotinic acetylcholine receptor binding.
Methyllycaconitine (MLA, 1) is a novel, potent probe for mammalian and insect nicotinic acetylcholine receptors (nAChR) and displays remarkable selectivity toward neuronal [125I]-alpha-bungarotoxin (alpha BgTX) binding sites that correspond to alpha 7-type nAChR in mammalian brain. We have shown that, among a number of selected norditerpenoid alkaloids, elatine (2) and nudicauline (3) are equipotent with, or better than, MLA (1) in binding to brain [125I]-alpha BgTX binding sites, with IC50 values of 6.1, 1.7, and 7.6 nM, respectively. The 2-((S)-methylsuccinimido)benzoyl moiety of these ligands is crucial for high-affinity binding, whereas structural modifications to the norditerpenoid core of the ligand can be tolerated without loss of activity or selectivity. In addition to MLA (1), elatine (2), and nudicauline (3), we have examined lycoctonine (4), inuline (6), lappaconitine (7), N-desacetyllappaconitine (8), delsoline (10), delcorine (11), deltaline (12), condelphine (13), and karacoline (14). This study therefore extends the range of norditerpenoids, other than MLA, which can be used to probe this important class of nAChR. All 12 alkaloids were assessed for activity at [3H]nicotine binding sites which are considered to represent alpha 4 beta 2 nAChR. Furthermore, the 1H and 13C NMR spectroscopic data of MLA and elatine have been critically compared.
Hardick
D J
DJ
Department of Medicinal Chemistry, School of Pharmacy and Pharmacology, Bath, U.K.
Blagbrough
I S
IS
Cooper
G
G
Potter
B V
BV
Critchley
T
T
Wonnacott
S
S
D000157:Aconitine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002038:Bungarotoxins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D011485:Protein Binding; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013388:Succinimides / Q000737:chemistry / Q000378:metabolism
D000470:Alkaloids; D002038:Bungarotoxins; D011978:Receptors, Nicotinic; D013388:Succinimides; C054634:methyllycaconitine; D000157:Aconitine