Bisquaternary caracurine V and iso-caracurine V salts as ligands for the muscle type of nicotinic acetylcholine receptors: SAR and QSAR studies.
The binding constants (K(i) values) of 24 caracurine V and 6 iso-caracurine V analogues for the muscle type of nicotinic ACh receptors (nAChR) from Torpedo californica were determined in a binding assay using (+/-)-[(3)H]epibatidine as a radioligand. The allyl alcohol group present in the iso-caracurine V ring system was found to be essential for high binding affinity. The most potent compounds are the dimethyl and di-(4-nitrobenzyl)-iso-caracurinium V salts 29 (18 nM), and 31 (79 nM), respectively. Compound 29 and the corresponding diallyl analogue 30 (350 nM) exhibited similar binding affinities as the equally substituted neuromuscular-blocking agents toxiferine I (14 nM) and alcuronium (234 nM), respectively. The SAR results were confirmed by QSAR studies, which additionally revealed that the presence of hydrogen-bond acceptor groups close to the quaternary nitrogen, is detrimental for the nicotinic binding affinity. The diallyl- and dimethylcaracurinium V salts 13 and 27, respectively, which are known to be among the most potent allosteric modulators of M(2) receptors (EC(50)=10 and 8nM, respectively), exhibited rather low nicotinic binding affinities for muscle type nAChR (K(i)=1.5 and 5.2 microM, respectively). Such a large difference in affinity suggests that it is possible to develop compounds with high muscarinic allosteric potency and low or negligible affinities for (alpha1)(2)beta1gammadelta nAChR. Additionally, the iso-caracurine V analogues with binding affinities comparable to those of (+)-tubocurarine and alcuronium could become a new class of neuromuscular-blocking agents.
Zlotos
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DP
Pharmaceutical Institute, University of Würzburg, Am Hubland, 97074 Würzburg, Germany. zlotos@pzlc.uni-wuerzburg.de
Gündisch
D
D
Ferraro
S
S
Tilotta
M C
MC
Stiefl
N
N
Baumann
K
K
D000470:Alkaloids / Q000737:chemistry*; D000495:Allosteric Site; D000818:Animals; D006860:Hydrogen Bonding; D007536:Isomerism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009132:Muscles; D009466:Neuromuscular Blocking Agents / Q000737:chemistry; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D043585:Receptor, Muscarinic M2 / Q000737:chemistry; D011978:Receptors, Nicotinic / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014101:Torpedo
D000470:Alkaloids; D008024:Ligands; D009466:Neuromuscular Blocking Agents; D043585:Receptor, Muscarinic M2; D011978:Receptors, Nicotinic; C041536:caracurine V