Abstract:
:PAC1 receptor is abundant in the CNS and plays an important role in neuronal survival. To identify the molecular determinants and the conformational components responsible for the activation of the PAC1 receptor, we performed a SAR study focusing on the N-terminal domain of its endogenous ligand, PACAP. This approach revealed that residues Asp(3) and Phe(6) are key elements of the pharmacophore of the PAC1 receptor. This study, supported by NMR structural analyses, suggests that the N-terminal tail of PACAP (residues 1 to 4) adopts a specific conformation similar to a turn when it activates the PAC1 receptor. Moreover, the integrity of the alpha-helix conformation observed at positions 5 to 7 appears crucial to allow the binding of PACAP. Characterization of analogues led to the identification of several superagonists, such as [Bip(6)]PACAP27, and of a new potent PAC1 receptor antagonist, [Sar(4)]PACAP38. The bioactive conformation inferred from this SAR study could constitute an appropriate molecular scaffold supporting the design of nonpeptidic PAC1 receptor agonists.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Bourgault S,Vaudry D,Ségalas-Milazzo I,Guilhaudis L,Couvineau A,Laburthe M,Vaudry H,Fournier Adoi
10.1021/jm900291jsubject
Has Abstractpub_date
2009-05-28 00:00:00pages
3308-16issue
10eissn
0022-2623issn
1520-4804journal_volume
52pub_type
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