Discovery and SAR of hydrazide antagonists of the pituitary adenylate cyclase-activating polypeptide (PACAP) receptor type 1 (PAC1-R)

Beebe, Xenia; Darczak, Daria; Davis-Taber, Rachel; Uchic, Marie E.; Scott, Victoria E.; Jarvis, Michael F.; Stewart, Andrew O.

doi:10.1016/j.bmcl.2008.01.052

Cited by 31 publications

(31 citation statements)

References 13 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, class B GPCRs are actually considered as difficult targets for drug development given that, despite their therapeutic interest, the identification of small molecules that can mimic the biological action of their large peptide ligands has been so far unsuccessful. As a matter of fact, in contrast to class A GPCRs, nonpeptide ligands acting as potent agonists have not been identified and nonpeptide antagonists have only been described for a small number of class B receptors [180][181][182]. Unfortunately, like PACAP, agonists are mostly needed for clinical applications, such as PTH for osteoporosis [183] and GLP-1 for type II diabetes [117].…”

Section: Resultsmentioning

confidence: 99%

Pituitary Adenylate Cyclase-Activating Polypeptide: Focus on Structure- Activity Relationships of a Neuroprotective Peptide

Bourgault¹,

Vaudry²,

Dejda³

et al. 2009

CMC

View full text Add to dashboard Cite

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a 38-amino acid peptide that was initially isolated from hypothalamus extracts on the basis of its ability to stimulate the production of cAMP in cultured pituitary cells. Recent studies have shown that PACAP exerts potent neuroprotective effects not only in vitro but also in in vivo models of Parkinson's disease, Huntington's disease, traumatic brain injury and stroke. The protective effects of PACAP are based on its capacity to prevent neuronal apoptosis by acting directly on neurons or indirectly through the release of neuroprotective factors by astrocytes. These biological activities are mainly mediated through activation of the PAC1 receptor which is currently considered as a potential target for the treatment of neurodegenerative diseases. However, the use of native PACAP, the endogenous ligand of PAC1, as an efficient neuroprotective drug is actually limited by its rapid degradation. Moreover, injection of PACAP to human induces peripheral side effects which are mainly mediated through VPAC1 and VPAC2 receptors. Strategies to overcome these compromising conditions include the development of metabolically stable analogs of PACAP acting as selective agonists of the PAC1 receptor. This review presents an overview of the structure-activity relationships of PACAP and summarizes the molecular and conformational requirements for activation of PAC1 receptor. The applicability of PACAP analogs as therapeutic agents for treatment of neurodegenerative diseases is also discussed.

show abstract

Section: Resultsmentioning

confidence: 99%

Pituitary Adenylate Cyclase-Activating Polypeptide: Focus on Structure- Activity Relationships of a Neuroprotective Peptide

Bourgault¹,

Vaudry²,

Dejda³

et al. 2009

CMC

View full text Add to dashboard Cite

show abstract

“…Further N-terminal shortening produced derivatives that acted again as agonists (Vandermeers et al 1992). Most recently, novel synthetic agonists and PACAP derivatives that show PAC1 receptor activation have been developed (Beebe et al 2008;Bourgault et al 2008).…”

Section: Discussionmentioning

confidence: 98%

Agonistic Behavior of PACAP6-38 on Sensory Nerve Terminals and Cytotrophoblast Cells

et al. 2008

View full text Add to dashboard Cite

The effects of pituitary adenylate cyclase activating polypeptide (PACAP) are mediated through G-protein-coupled receptors, the specific PAC1 receptor and VPAC1 and VPAC2 receptors which bind vasoactive intestinal peptide with similar affinity. Based on binding affinity studies, PACAP6-38 was discovered as a potent antagonist of PAC1 and it has been used by hundreds of studies as a PACAP antagonist. Recently, we have found that in certain cells/tissues, PACAP6-38 does not antagonize PACAP-induced effects, but surprisingly, it exerts similar actions to PACAP1-38, behaving as an agonist. In the present study, we report on the agonistic behavior of PACAP6-38 on neuropeptide release from sensory nerves of the isolated rat trachea and on the MAPK signaling pathways in cytotrophoblast cells. In isolated rat tracheae, PACAP6-38, similarly to PACAP1-38, induced significant inhibitory effects on the release of three simultaneously measured sensory neuropeptides, substance P, calcitonin gene-related peptide, and somatostatin evoked by both chemical excitation and electrical field stimulation of capsaicin-sensitive afferents. Effects of PACAP6-38 were the same as those of PACAP1-38 on MAPK signaling in human cytotrophoblast cells. Western blot analysis showed that both peptide forms stimulated ERK1/2 and JNK phosphorylation, while they both inhibited p38 MAPK phosphorylation. The most pronounced effects were observed when both peptides were present. In summary, our results show that PACAP6-38, which is a PACAP receptor antagonist in most cells/tissues, can behave as an agonist in other systems. The increasing interest in the effects of PACAP requires further studies on the pharmacological properties of the peptide and its analogues.

show abstract

“…The discovery of non-peptidic small molecule agonists for the PAC1 receptor would be an alternative. Such molecules have not been identified yet but, interestingly, the screening of the Abbott compound library has recently led to the identification of two acyl hydrazides that bind to the PAC1 receptor and behave as antagonists (Beebe et al 2008). This information, together with recent progress in the mechanisms involved in the molecular activation of the PAC1 receptor (Sun et al 2007), should provide important clues for the rational design of non-peptidic PACAP agonists.…”

Section: Perspectives-pacap As a Pharmacological Tool Against Neuronamentioning

confidence: 98%

Inhibitory Effect of PACAP on Caspase Activity in Neuronal Apoptosis: A Better Understanding Towards Therapeutic Applications in Neurodegenerative Diseases

et al. 2008

View full text Add to dashboard Cite

Programmed cell death, which is part of the normal development of the central nervous system, is also implicated in various neurodegenerative disorders. Cysteine-dependent aspartate-specific proteases (caspases) play a pivotal role in the cascade of events leading to apoptosis. Many factors that inhibit cell death have now been identified, but the underlying mechanisms are not fully understood. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to exert neurotrophic activities during development and to prevent neuronal apoptosis induced by various insults such as ischemia. Most of the neuroprotective effects of PACAP are mediated through the PAC1 receptor. This receptor activates a transduction cascade of second messengers to stimulate Bcl-2 expression, which inhibits cytochrome c release and blocks the activation of caspases. The inhibitory effect of PACAP on the apoptotic cascade suggests that selective, stable, and potent PACAP derivatives could potentially be of therapeutic value for the treatment of post-traumatic and/or chronic neurodegenerative processes.

show abstract

Discovery and SAR of hydrazide antagonists of the pituitary adenylate cyclase-activating polypeptide (PACAP) receptor type 1 (PAC1-R)

Cited by 31 publications

References 13 publications

Pituitary Adenylate Cyclase-Activating Polypeptide: Focus on Structure- Activity Relationships of a Neuroprotective Peptide

Pituitary Adenylate Cyclase-Activating Polypeptide: Focus on Structure- Activity Relationships of a Neuroprotective Peptide

Agonistic Behavior of PACAP6-38 on Sensory Nerve Terminals and Cytotrophoblast Cells

Inhibitory Effect of PACAP on Caspase Activity in Neuronal Apoptosis: A Better Understanding Towards Therapeutic Applications in Neurodegenerative Diseases

Contact Info

Product

Resources

About