Molecular probes for muscarinic receptors: Functionalized congeners of selective muscarinic antagonists

Kenneth A. Jacobson, Bilha Fischer, A. Michiel van Rhee

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


The muscarinic agonist oxotremorine and the tricyclic muscarinic antagonists pirenzepine and telenzepine have been derivatized using a functionalized congener approach for the purpose of synthesizing high affinity ligand probes that are suitable for conjugation with prosthetic groups, for receptor cross-linking, fluorescent and radioactive detection, etc. A novel fluorescent conjugate of TAC (telenzepine amine congener), an n-decylamino derivative of the m1-selective antagonist, with the fluorescent trisulfonated pyrene dye Cascade Blue may be useful for assaying the receptor as an alternative to radiotracers. In a rat m3 receptor mutant containing a single amino acid substitution in the sixth transmembrane domain (Asn507 to Ala) the parent telenzepine lost 636-fold in affinity, while TAC lost only 27-fold. Thus, the decylamino group of TAC stabilizes the bound state and thus enhances potency by acting as a distal anchor in the receptor binding site. We have built a computer-assisted molecular model of the transmembrane regions of muscarinic receptors based on homology with the G-protein coupled receptor rhodopsin, for which a low resolution structure is known. We have coordinated the antagonist pharmacophore (tricyclic and piperazine moieties) with residues of the third and seventh helices of the rat m3 receptor. Although the decylamino chain of TAC is likely to be highly flexible and may adopt many conformations, we located one possible site for a salt bridge formation with the positively charged -NH3+ group, i.e. Asp 113 in helix II.

Original languageEnglish
Pages (from-to)823-830
Number of pages8
JournalLife Sciences
Issue number11-12
StatePublished - 10 Feb 1995
Externally publishedYes

Bibliographical note

Funding Information:
We thank Dr. Yishai Karton (IIBR) for helpful discussions and Dr. Jiirgen Wess (NIDDK) for binding studies on mutant m3 receptorsa nd for helpful discussions. TAC was provided by RBI (Natick MA) in the Chemical Synthesis Program of NIMH contract NOlMH30003. We thank Drs. R. Tyler McCabe and Bryan R.Wilson of PharmaceuticalD iscovery Corporation, Elmsford, NY for performing initial binding experimentso n Cascadeb lue-TAC.


  • G-protein coupled receptors
  • fluorescence
  • molecular modeling
  • telenzepine


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