Syntheses and biological properties of cysteine-reactive epibatidine derivatives.
The synthesis of epibatidine derivatives modified at the 2-position of the pyridine or pyrimidine rings by reactive functions are described for potential irreversible site-directed coupling reactions on cysteine mutants of neuronal nicotinic acetylcholine receptors. An improved synthesis of the 7-azabicyclo[2,2,1]hepta-2,5-diene key intermediate has been developed to allow reproducible syntheses of the epibatidine derivatives. Binding tests and electrophysiological experiments allowed to select the 2-substituted alpha-chloroacetamido 13 and the chloropyrimidine derivative 11 as potential site-directed probes for the epibatidine binding site.
Che
Christian
C
Laboratoire de Chimie Bioorganique, UMR 7514 CNRS, Faculté de Pharmacie, Université Louis Pasteur Strasbourg BP 24, 67401 Illkirch, cedex France.
Petit
Grégory
G
Kotzyba-Hibert
Florence
F
Bertrand
Sonia
S
Bertrand
Daniel
D
Grutter
Thomas
T
Goeldner
Maurice
M
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D003545:Cysteine / Q000737:chemistry*; D008564:Membrane Potentials / Q000187:drug effects; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018722:Nicotinic Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000378:metabolism
D019086:Bridged Bicyclo Compounds, Heterocyclic; D018722:Nicotinic Agonists; D011725:Pyridines; D011743:Pyrimidines; D011978:Receptors, Nicotinic; D011993:Recombinant Fusion Proteins; D003545:Cysteine; C082748:epibatidine