Design and in vitro characterization of PAC1/VPAC1-selective agonists with potent neuroprotective effects.
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic neuropeptide that exerts a large array of actions in the central nervous system and periphery. Through the activation of PAC1 and VPAC1, PACAP is able to exert neuroprotective, as well as anti-inflammatory effects, two phenomena involved in the pathogenesis and the progression of neurodegenerative diseases. The aim of the current study was to provide insights into the molecular arrangement of the amino terminus of PACAP and to develop new potent and selective PAC1/VPAC1 agonists promoting neuronal survival. We have synthesized a series of PACAP derivatives and measured their binding affinity and their ability to induce intracellular calcium mobilization for each receptor, i.e. PAC1, VPAC1, and VPAC2. Ultimately, analogs with an improved pharmacological profile were evaluated in an in vitro model of neuronal loss. Results showed that introduction of a hydroxyproline or an alanine moiety, respectively, at position 2 or 7 generated derivatives without significant VPAC2 agonistic activity. Moreover, the structure-activity relationship study suggests the presence of common (Asx-turn like) and distinct (different N-capping type) secondary structures that might be responsible for receptor recognition, selectivity and activation. Finally, evaluation of the neuroprotective activity of [Ala(7)]PACAP27 and [Hyp(2)]PACAP27 demonstrated their ability to protect potently human dopaminergic SH-SY5Y neuroblasts against the toxicity of MPP(+), in pre- and co-treatment experiments. These new pharmacological and structural data should prove useful for the rational design of PACAP-derived compounds that could be putative therapeutic agents for the treatment of neurodegenerative diseases.
Institut Armand-Frappier, Institut National de la Recherche Scientifique, Université du Québec, 531 boulevard des Prairies, Ville de Laval, Québec H7V 1B7, Canada.
Ngoc-Duc
ND
Doan
Steve
S
Bourgault
Agnieszka
A
Dejda
Myriam
M
Létourneau
Michel
M
Detheux
David
D
Vaudry
Hubert
H
Vaudry
David
D
Chatenet
Alain
A
Fournier
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000737:chemistry*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I / Q000819:agonists*; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000819:agonists*; D013329:Structure-Activity Relationship; D014162:Transfection
D018696:Neuroprotective Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D051237:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I