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Synthesis of novel and functionally selective non-competitive muscarinic antagonists as chemical probes

Synthesis of novel and functionally selective non-competitive muscarinic antagonists as chemical probes Core structure of novel muscarinic antagonists

In collaboration with Barry University novel muscarinic antagonists were developed.

Muscarinic receptors are known to play important biological roles and are drug targets for several human diseases. In a pilot study, novel muscarinic antagonists were synthesized and used as chemical probes to obtain additional information of the muscarinic pharmacophore. The design of these ligands made use of current orthosteric and allosteric models of drug-receptor interactions together with chemical motifs known to achieve muscarinic receptor selectivity. This approach has led to the discovery of several non-competitive muscarinic ligands that strongly bind at a secondary receptor site. These compounds were found to be non-competitive antagonists that completely abolished carbachol activation in functional assays. Several of these compounds antagonized functional response to carbachol with great potency at M1 and M4 than at the rest of receptor subtypes.

Contacts

Institute of Physiology AS CR, v.v.i.
Department of Neurochemistry

Vídeňská 1083
14220 Prague 4
tel. +420 241 062 620
fax. +420 241 062 488
   

jakubik@biomed.cas.cz

People

  Mgr. Jan Jakubík, Ph.D.
head of the department
  MUDr. Vladimír Doležal, DrSc.
deputy head of the department
  RNDr. Vladimír Rudajev Ph.D.
senior researcher
  MUDr. et Mgr. Helena Janíčková, Ph.D.
postdoc
  Mgr. Alena Randáková, Ph.D.
postdoc
  Mgr. Eva Dolejší, Ph.D.
postdoc (maternity leave)
  Romana Ondřejová
technician
  Dana Ungerová
technician

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