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The Pharmacophoric Determinants of PACAP

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Pituitary Adenylate Cyclase Activating Polypeptide — PACAP

Part of the book series: Current Topics in Neurotoxicity ((Current Topics Neurotoxicity,volume 11))

Abstract

The pituitary adenylate cyclase-activating polypeptide (PACAP) is a hormone that belongs to the secretin/glucagon/growth hormone-releasing hormone (GHRH)/vasoactive intestinal peptide (VIP) superfamily. It shows a widespread distribution and a large array of physiological actions. Accordingly, this peptide is linked to various pathological conditions and PACAP-derived drugs are promising compounds for the development of potent therapies. The effects of PACAP are mediated through three types of class B-G protein-coupled receptors identified as PAC1, VPAC1, and VPAC2. PACAP exhibits a larger affinity for PAC1 than VIP, whereas VPAC1 and VPAC2 are equally recognized by both ligands. The three receptors possess distinct pharmacophoric requirements and in particular, residues His1, Asp3, Phe6, Thr7, Tyr22, and Leu23, as well as structural motifs such as a highly stabilized α-helix and an N-terminal β-coil abutted to an N-capping-like arrangement, would be crucial for receptor selectivity. Moreover, PACAP is vulnerable to proteolysis and sites of enzymatic degradation were identified to develop metabolically stable compounds. The present review summarizes structure–activity relationships of PACAP and makes an overview of the conformational features of the molecule.

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Abbreviations

Aad:

l-α-aminoadipic acid

Aca:

Aminocaproic acid

BBB:

Blood–brain barrier

Bip:

l-biphenylalanine

Bpa:

p-benzoyl-l-phenylalanine

CT:

Calcitonin

Disc:

l-1,3-dihydro-2H-isoindole carboxylic acid

GLP-1:

Glucagon-like peptide-1

GPCR(s):

G protein-coupled receptor(s)

Hyp:

Hydroxyproline

Iaa:

4-Imidazole acetic acid

Iac:

4-Imidazole acrylic acid

R-IBTM:

2(R)-amino-3-oxohexahydroindolizino[8,7-b]indole-5(R)-carboxylic acid

S-IBTM:

2(S)-amino-3-oxohexahydroindolizino[8,7-b]indole-5(S)-carboxylic acid

Ind:

l-indoline-2-carboxylic acid

Nal:

l-naphthylalanine

Nle:

l-norleucine

NOESY:

Nuclear Overhauser Effect spectroscopy

PACAP:

Pituitary adenylate cyclase-activating polypeptide

PACAP27:

27-amino acid isoform of PACAP

PACAP38:

38-amino acid isoform of PACAP

PAC1:

Pituitary adenylate cyclase-activating polypeptide type 1 receptor

Phe(p-I):

Para-iodo-l-phenylalanine

PTH:

Parathyroid hormone

PTS-6:

Peptide transport system-6

SAR:

Structure–activity relationships

TFE:

Trifluoroethanol

Tic:

l-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

Tiq:

l-tetrahydroisoquinoline-1-carboxylic acid

VIP:

Vasoactive intestinal peptide

VPAC1:

VIP/PACAP type 1 receptor

VPAC2:

VIP/PACAP type 2 receptor

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Acknowledgements

This work was supported by the Canadian Institutes of Health Research (AF; FRN102734), the Fonds de recherche du Québec-Nature et technologies (DC; 1888882), and the Natural Sciences and Engineering Research Council of Canada (SB; 1557119).

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Authors and Affiliations

  1. Laboratoire d’études moléculaires et pharmacologiques des peptides, Institut national de la recherche scientifique, INRS — Institut Armand-Frappier, 531 boul. des Prairies, Laval, QC, Canada, H7V 1B7

    Alain Fournier

  2. Département de Chimie, Université du Québec à Montréal, C.P. 8888, Succ. Centre-Ville, Montréal, QC, Canada, H3C 3P8

    Steve Bourgault

  3. Quebec Network for Research on Protein Function, Engineering and Applications, PROTEO, Québec, QC, Canada

    Steve Bourgault

  4. Groupe de Recherche en Ingénierie des Peptides et en Pharmacothérapie, Institut national de la recherche scientifique, INRS — Institut Armand-Frappier, 531 boul. des Prairies, Laval, QC, Canada, H7V 1B7

    David Chatenet

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  1. Alain Fournier
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  2. Steve Bourgault
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  3. David Chatenet
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Corresponding author

Correspondence to Alain Fournier .

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Editors and Affiliations

  1. Department of Anatomy MTA-PTE “Lendulet” PACAP Research Team, University of Pecs, Pecs, Hungary

    Dora Reglodi

  2. Department of Anatomy MTA-PTE “Lendulet” PACAP Research Team, University of Pecs, Pecs, Hungary

    Andrea Tamas

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Fournier, A., Bourgault, S., Chatenet, D. (2016). The Pharmacophoric Determinants of PACAP. In: Reglodi, D., Tamas, A. (eds) Pituitary Adenylate Cyclase Activating Polypeptide — PACAP. Current Topics in Neurotoxicity, vol 11. Springer, Cham. https://doi.org/10.1007/978-3-319-35135-3_8

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