Design and in vitro characterization of PAC1/VPAC1-selective agonists with potent neuroprotective effects
Identifieur interne : 000342 ( PascalFrancis/Corpus ); précédent : 000341; suivant : 000343Design and in vitro characterization of PAC1/VPAC1-selective agonists with potent neuroprotective effects
Auteurs : Ngoc-Duc Doan ; Steve Bourgault ; Agnieszka Dejda ; Myriam Letourneau ; Michel Detheux ; David Vaudry ; Hubert Vaudry ; David Chatenet ; Alain FournierSource :
- Biochemical pharmacology [ 0006-2952 ] ; 2011.
Descripteurs français
- Pascal (Inist)
English descriptors
- KwdEn :
Abstract
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 [Ala7]PACAP27 and [Hyp2]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.
Notice en format standard (ISO 2709)
Pour connaître la documentation sur le format Inist Standard.
| pA |
|
|---|
Format Inist (serveur)
| NO : | PASCAL 11-0143203 INIST |
|---|---|
| ET : | Design and in vitro characterization of PAC1/VPAC1-selective agonists with potent neuroprotective effects |
| AU : | DOAN (Ngoc-Duc); BOURGAULT (Steve); DEJDA (Agnieszka); LETOURNEAU (Myriam); DETHEUX (Michel); VAUDRY (David); VAUDRY (Hubert); CHATENET (David); FOURNIER (Alain) |
| AF : | Institut Armand-Frappier, Institut National de la Recherche Scientifique, Université du Québec, 531 boulevard des Prairies, Ville de Laval/Québec H7V 1B7/Canada (1 aut., 2 aut., 3 aut., 4 aut., 8 aut., 9 aut.); Laboratoire International Associé Samuel de Champlain INSERM - INRS/France/Canada (1 aut., 2 aut., 3 aut., 4 aut., 6 aut., 7 aut., 8 aut., 9 aut.); Euroscreen S.A., 47 Rue Adrienne Bolland/6041 Gosselies/Belgique (5 aut.); INSERM-U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, IFRMP 23, Université de Rouen/76821 Mont-Saint-Aignan/France (6 aut., 7 aut.) |
| DT : | Publication en série; Niveau analytique |
| SO : | Biochemical pharmacology; ISSN 0006-2952; Coden BCPCA6; Pays-Bas; Da. 2011; Vol. 81; No. 4; Pp. 552-561; Bibl. 43 ref. |
| LA : | Anglais |
| EA : | 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 [Ala7]PACAP27 and [Hyp2]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. |
| CC : | 002B02; 002B17G; 002B17A01 |
| FD : | In vitro; Caractérisation; Agoniste; Neuroprotection; Neuroprotecteur; Peptide PACAP; Relation structure activité; Sélectivité; Maladie de Parkinson |
| FG : | Neuropeptide; Maladie dégénérative; Pathologie du système nerveux; Pathologie de l'encéphale; Syndrome extrapyramidal; Pathologie du système nerveux central |
| ED : | In vitro; Characterization; Agonist; Neuroprotection; Neuroprotective agent; Pituitary adenylate cyclase activating peptide; Structure activity relation; Selectivity; Parkinson disease |
| EG : | Neuropeptide; Degenerative disease; Nervous system diseases; Cerebral disorder; Extrapyramidal syndrome; Central nervous system disease |
| SD : | In vitro; Caracterización; Agonista; Neuroprotección; Neuroprotector; Péptido PACAP; Relación estructura actividad; Selectividad; Parkinson enfermedad |
| LO : | INIST-1418.354000193708330100 |
| ID : | 11-0143203 |
Links to Exploration step
Pascal:11-0143203Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en" level="a">Design and in vitro characterization of PAC1/VPAC1-selective agonists with potent neuroprotective effects</title><author><name sortKey="Doan, Ngoc Duc" sort="Doan, Ngoc Duc" uniqKey="Doan N" first="Ngoc-Duc" last="Doan">Ngoc-Duc Doan</name><affiliation><inist:fA14 i1="01"><s1>Institut Armand-Frappier, Institut National de la Recherche Scientifique, Université du Québec, 531 boulevard des Prairies, Ville de Laval</s1><s2>Québec H7V 1B7</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="02"><s1>Laboratoire International Associé Samuel de Champlain INSERM - INRS</s1><s2>France</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Bourgault, Steve" sort="Bourgault, Steve" uniqKey="Bourgault S" first="Steve" last="Bourgault">Steve Bourgault</name><affiliation><inist:fA14 i1="01"><s1>Institut Armand-Frappier, Institut National de la Recherche Scientifique, Université du Québec, 531 boulevard des Prairies, Ville de Laval</s1><s2>Québec H7V 1B7</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="02"><s1>Laboratoire International Associé Samuel de Champlain INSERM - INRS</s1><s2>France</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Dejda, Agnieszka" sort="Dejda, Agnieszka" uniqKey="Dejda A" first="Agnieszka" last="Dejda">Agnieszka Dejda</name><affiliation><inist:fA14 i1="01"><s1>Institut Armand-Frappier, Institut National de la Recherche Scientifique, Université du Québec, 531 boulevard des Prairies, Ville de Laval</s1><s2>Québec H7V 1B7</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="02"><s1>Laboratoire International Associé Samuel de Champlain INSERM - INRS</s1><s2>France</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Letourneau, Myriam" sort="Letourneau, Myriam" uniqKey="Letourneau M" first="Myriam" last="Letourneau">Myriam Letourneau</name><affiliation><inist:fA14 i1="01"><s1>Institut Armand-Frappier, Institut National de la Recherche Scientifique, Université du Québec, 531 boulevard des Prairies, Ville de Laval</s1><s2>Québec H7V 1B7</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="02"><s1>Laboratoire International Associé Samuel de Champlain INSERM - INRS</s1><s2>France</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Detheux, Michel" sort="Detheux, Michel" uniqKey="Detheux M" first="Michel" last="Detheux">Michel Detheux</name><affiliation><inist:fA14 i1="03"><s1>Euroscreen S.A., 47 Rue Adrienne Bolland</s1><s2>6041 Gosselies</s2><s3>BEL</s3><sZ>5 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Vaudry, David" sort="Vaudry, David" uniqKey="Vaudry D" first="David" last="Vaudry">David Vaudry</name><affiliation><inist:fA14 i1="02"><s1>Laboratoire International Associé Samuel de Champlain INSERM - INRS</s1><s2>France</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="04"><s1>INSERM-U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, IFRMP 23, Université de Rouen</s1><s2>76821 Mont-Saint-Aignan</s2><s3>FRA</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Vaudry, Hubert" sort="Vaudry, Hubert" uniqKey="Vaudry H" first="Hubert" last="Vaudry">Hubert Vaudry</name><affiliation><inist:fA14 i1="02"><s1>Laboratoire International Associé Samuel de Champlain INSERM - INRS</s1><s2>France</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="04"><s1>INSERM-U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, IFRMP 23, Université de Rouen</s1><s2>76821 Mont-Saint-Aignan</s2><s3>FRA</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Chatenet, David" sort="Chatenet, David" uniqKey="Chatenet D" first="David" last="Chatenet">David Chatenet</name><affiliation><inist:fA14 i1="01"><s1>Institut Armand-Frappier, Institut National de la Recherche Scientifique, Université du Québec, 531 boulevard des Prairies, Ville de Laval</s1><s2>Québec H7V 1B7</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="02"><s1>Laboratoire International Associé Samuel de Champlain INSERM - INRS</s1><s2>France</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Fournier, Alain" sort="Fournier, Alain" uniqKey="Fournier A" first="Alain" last="Fournier">Alain Fournier</name><affiliation><inist:fA14 i1="01"><s1>Institut Armand-Frappier, Institut National de la Recherche Scientifique, Université du Québec, 531 boulevard des Prairies, Ville de Laval</s1><s2>Québec H7V 1B7</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="02"><s1>Laboratoire International Associé Samuel de Champlain INSERM - INRS</s1><s2>France</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">INIST</idno><idno type="inist">11-0143203</idno><date when="2011">2011</date><idno type="stanalyst">PASCAL 11-0143203 INIST</idno><idno type="RBID">Pascal:11-0143203</idno><idno type="wicri:Area/PascalFrancis/Corpus">000342</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a">Design and in vitro characterization of PAC1/VPAC1-selective agonists with potent neuroprotective effects</title><author><name sortKey="Doan, Ngoc Duc" sort="Doan, Ngoc Duc" uniqKey="Doan N" first="Ngoc-Duc" last="Doan">Ngoc-Duc Doan</name><affiliation><inist:fA14 i1="01"><s1>Institut Armand-Frappier, Institut National de la Recherche Scientifique, Université du Québec, 531 boulevard des Prairies, Ville de Laval</s1><s2>Québec H7V 1B7</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="02"><s1>Laboratoire International Associé Samuel de Champlain INSERM - INRS</s1><s2>France</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Bourgault, Steve" sort="Bourgault, Steve" uniqKey="Bourgault S" first="Steve" last="Bourgault">Steve Bourgault</name><affiliation><inist:fA14 i1="01"><s1>Institut Armand-Frappier, Institut National de la Recherche Scientifique, Université du Québec, 531 boulevard des Prairies, Ville de Laval</s1><s2>Québec H7V 1B7</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="02"><s1>Laboratoire International Associé Samuel de Champlain INSERM - INRS</s1><s2>France</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Dejda, Agnieszka" sort="Dejda, Agnieszka" uniqKey="Dejda A" first="Agnieszka" last="Dejda">Agnieszka Dejda</name><affiliation><inist:fA14 i1="01"><s1>Institut Armand-Frappier, Institut National de la Recherche Scientifique, Université du Québec, 531 boulevard des Prairies, Ville de Laval</s1><s2>Québec H7V 1B7</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="02"><s1>Laboratoire International Associé Samuel de Champlain INSERM - INRS</s1><s2>France</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Letourneau, Myriam" sort="Letourneau, Myriam" uniqKey="Letourneau M" first="Myriam" last="Letourneau">Myriam Letourneau</name><affiliation><inist:fA14 i1="01"><s1>Institut Armand-Frappier, Institut National de la Recherche Scientifique, Université du Québec, 531 boulevard des Prairies, Ville de Laval</s1><s2>Québec H7V 1B7</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="02"><s1>Laboratoire International Associé Samuel de Champlain INSERM - INRS</s1><s2>France</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Detheux, Michel" sort="Detheux, Michel" uniqKey="Detheux M" first="Michel" last="Detheux">Michel Detheux</name><affiliation><inist:fA14 i1="03"><s1>Euroscreen S.A., 47 Rue Adrienne Bolland</s1><s2>6041 Gosselies</s2><s3>BEL</s3><sZ>5 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Vaudry, David" sort="Vaudry, David" uniqKey="Vaudry D" first="David" last="Vaudry">David Vaudry</name><affiliation><inist:fA14 i1="02"><s1>Laboratoire International Associé Samuel de Champlain INSERM - INRS</s1><s2>France</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="04"><s1>INSERM-U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, IFRMP 23, Université de Rouen</s1><s2>76821 Mont-Saint-Aignan</s2><s3>FRA</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Vaudry, Hubert" sort="Vaudry, Hubert" uniqKey="Vaudry H" first="Hubert" last="Vaudry">Hubert Vaudry</name><affiliation><inist:fA14 i1="02"><s1>Laboratoire International Associé Samuel de Champlain INSERM - INRS</s1><s2>France</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="04"><s1>INSERM-U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, IFRMP 23, Université de Rouen</s1><s2>76821 Mont-Saint-Aignan</s2><s3>FRA</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Chatenet, David" sort="Chatenet, David" uniqKey="Chatenet D" first="David" last="Chatenet">David Chatenet</name><affiliation><inist:fA14 i1="01"><s1>Institut Armand-Frappier, Institut National de la Recherche Scientifique, Université du Québec, 531 boulevard des Prairies, Ville de Laval</s1><s2>Québec H7V 1B7</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="02"><s1>Laboratoire International Associé Samuel de Champlain INSERM - INRS</s1><s2>France</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation></author><author><name sortKey="Fournier, Alain" sort="Fournier, Alain" uniqKey="Fournier A" first="Alain" last="Fournier">Alain Fournier</name><affiliation><inist:fA14 i1="01"><s1>Institut Armand-Frappier, Institut National de la Recherche Scientifique, Université du Québec, 531 boulevard des Prairies, Ville de Laval</s1><s2>Québec H7V 1B7</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation><affiliation><inist:fA14 i1="02"><s1>Laboratoire International Associé Samuel de Champlain INSERM - INRS</s1><s2>France</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></inist:fA14></affiliation></author></analytic><series><title level="j" type="main">Biochemical pharmacology</title><title level="j" type="abbreviated">Biochem. pharmacol.</title><idno type="ISSN">0006-2952</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Biochemical pharmacology</title><title level="j" type="abbreviated">Biochem. pharmacol.</title><idno type="ISSN">0006-2952</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Agonist</term><term>Characterization</term><term>In vitro</term><term>Neuroprotection</term><term>Neuroprotective agent</term><term>Parkinson disease</term><term>Pituitary adenylate cyclase activating peptide</term><term>Selectivity</term><term>Structure activity relation</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>In vitro</term><term>Caractérisation</term><term>Agoniste</term><term>Neuroprotection</term><term>Neuroprotecteur</term><term>Peptide PACAP</term><term>Relation structure activité</term><term>Sélectivité</term><term>Maladie de Parkinson</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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<sup>7</sup>]PACAP27 and [Hyp<sup>2</sup>]PACAP27 demonstrated their ability to protect potently human dopaminergic SH-SY5Y neuroblasts against the toxicity of MPP<sup>+</sup>, 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.</div></front></TEI><inist><standard h6="B"><pA><fA01 i1="01" i2="1"><s0>0006-2952</s0></fA01><fA02 i1="01"><s0>BCPCA6</s0></fA02><fA03 i2="1"><s0>Biochem. pharmacol.</s0></fA03><fA05><s2>81</s2></fA05><fA06><s2>4</s2></fA06><fA08 i1="01" i2="1" l="ENG"><s1>Design and in vitro characterization of PAC1/VPAC1-selective agonists with potent neuroprotective effects</s1></fA08><fA11 i1="01" i2="1"><s1>DOAN (Ngoc-Duc)</s1></fA11><fA11 i1="02" i2="1"><s1>BOURGAULT (Steve)</s1></fA11><fA11 i1="03" i2="1"><s1>DEJDA (Agnieszka)</s1></fA11><fA11 i1="04" i2="1"><s1>LETOURNEAU (Myriam)</s1></fA11><fA11 i1="05" i2="1"><s1>DETHEUX (Michel)</s1></fA11><fA11 i1="06" i2="1"><s1>VAUDRY (David)</s1></fA11><fA11 i1="07" i2="1"><s1>VAUDRY (Hubert)</s1></fA11><fA11 i1="08" i2="1"><s1>CHATENET (David)</s1></fA11><fA11 i1="09" i2="1"><s1>FOURNIER (Alain)</s1></fA11><fA14 i1="01"><s1>Institut Armand-Frappier, Institut National de la Recherche Scientifique, Université du Québec, 531 boulevard des Prairies, Ville de Laval</s1><s2>Québec H7V 1B7</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></fA14><fA14 i1="02"><s1>Laboratoire International Associé Samuel de Champlain INSERM - INRS</s1><s2>France</s2><s3>CAN</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>6 aut.</sZ><sZ>7 aut.</sZ><sZ>8 aut.</sZ><sZ>9 aut.</sZ></fA14><fA14 i1="03"><s1>Euroscreen S.A., 47 Rue Adrienne Bolland</s1><s2>6041 Gosselies</s2><s3>BEL</s3><sZ>5 aut.</sZ></fA14><fA14 i1="04"><s1>INSERM-U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, IFRMP 23, Université de Rouen</s1><s2>76821 Mont-Saint-Aignan</s2><s3>FRA</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ></fA14><fA20><s1>552-561</s1></fA20><fA21><s1>2011</s1></fA21><fA23 i1="01"><s0>ENG</s0></fA23><fA43 i1="01"><s1>INIST</s1><s2>1418</s2><s5>354000193708330100</s5></fA43><fA44><s0>0000</s0><s1>© 2011 INIST-CNRS. All rights reserved.</s1></fA44><fA45><s0>43 ref.</s0></fA45><fA47 i1="01" i2="1"><s0>11-0143203</s0></fA47><fA60><s1>P</s1></fA60><fA61><s0>A</s0></fA61><fA64 i1="01" i2="1"><s0>Biochemical pharmacology</s0></fA64><fA66 i1="01"><s0>NLD</s0></fA66><fC01 i1="01" l="ENG"><s0>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<sup>7</sup>]PACAP27 and [Hyp<sup>2</sup>]PACAP27 demonstrated their ability to protect potently human dopaminergic SH-SY5Y neuroblasts against the toxicity of MPP<sup>+</sup>, 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.</s0></fC01><fC02 i1="01" i2="X"><s0>002B02</s0></fC02><fC02 i1="02" i2="X"><s0>002B17G</s0></fC02><fC02 i1="03" i2="X"><s0>002B17A01</s0></fC02><fC03 i1="01" i2="X" l="FRE"><s0>In vitro</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="ENG"><s0>In vitro</s0><s5>01</s5></fC03><fC03 i1="01" i2="X" l="SPA"><s0>In vitro</s0><s5>01</s5></fC03><fC03 i1="02" i2="X" l="FRE"><s0>Caractérisation</s0><s5>02</s5></fC03><fC03 i1="02" i2="X" l="ENG"><s0>Characterization</s0><s5>02</s5></fC03><fC03 i1="02" i2="X" l="SPA"><s0>Caracterización</s0><s5>02</s5></fC03><fC03 i1="03" i2="X" l="FRE"><s0>Agoniste</s0><s5>03</s5></fC03><fC03 i1="03" i2="X" l="ENG"><s0>Agonist</s0><s5>03</s5></fC03><fC03 i1="03" i2="X" l="SPA"><s0>Agonista</s0><s5>03</s5></fC03><fC03 i1="04" i2="X" l="FRE"><s0>Neuroprotection</s0><s5>04</s5></fC03><fC03 i1="04" i2="X" l="ENG"><s0>Neuroprotection</s0><s5>04</s5></fC03><fC03 i1="04" i2="X" l="SPA"><s0>Neuroprotección</s0><s5>04</s5></fC03><fC03 i1="05" i2="X" l="FRE"><s0>Neuroprotecteur</s0><s5>05</s5></fC03><fC03 i1="05" i2="X" l="ENG"><s0>Neuroprotective agent</s0><s5>05</s5></fC03><fC03 i1="05" i2="X" l="SPA"><s0>Neuroprotector</s0><s5>05</s5></fC03><fC03 i1="06" i2="X" l="FRE"><s0>Peptide PACAP</s0><s5>06</s5></fC03><fC03 i1="06" i2="X" l="ENG"><s0>Pituitary adenylate cyclase activating peptide</s0><s5>06</s5></fC03><fC03 i1="06" i2="X" l="SPA"><s0>Péptido PACAP</s0><s5>06</s5></fC03><fC03 i1="07" i2="X" l="FRE"><s0>Relation structure activité</s0><s5>07</s5></fC03><fC03 i1="07" i2="X" l="ENG"><s0>Structure activity relation</s0><s5>07</s5></fC03><fC03 i1="07" i2="X" l="SPA"><s0>Relación estructura actividad</s0><s5>07</s5></fC03><fC03 i1="08" i2="X" l="FRE"><s0>Sélectivité</s0><s5>08</s5></fC03><fC03 i1="08" i2="X" l="ENG"><s0>Selectivity</s0><s5>08</s5></fC03><fC03 i1="08" i2="X" l="SPA"><s0>Selectividad</s0><s5>08</s5></fC03><fC03 i1="09" i2="X" l="FRE"><s0>Maladie de Parkinson</s0><s2>NM</s2><s5>09</s5></fC03><fC03 i1="09" i2="X" l="ENG"><s0>Parkinson disease</s0><s2>NM</s2><s5>09</s5></fC03><fC03 i1="09" i2="X" l="SPA"><s0>Parkinson enfermedad</s0><s2>NM</s2><s5>09</s5></fC03><fC07 i1="01" i2="X" l="FRE"><s0>Neuropeptide</s0><s5>37</s5></fC07><fC07 i1="01" i2="X" l="ENG"><s0>Neuropeptide</s0><s5>37</s5></fC07><fC07 i1="01" i2="X" l="SPA"><s0>Neuropéptido</s0><s5>37</s5></fC07><fC07 i1="02" i2="X" l="FRE"><s0>Maladie dégénérative</s0><s5>38</s5></fC07><fC07 i1="02" i2="X" l="ENG"><s0>Degenerative disease</s0><s5>38</s5></fC07><fC07 i1="02" i2="X" l="SPA"><s0>Enfermedad degenerativa</s0><s5>38</s5></fC07><fC07 i1="03" i2="X" l="FRE"><s0>Pathologie du système nerveux</s0><s5>39</s5></fC07><fC07 i1="03" i2="X" l="ENG"><s0>Nervous system diseases</s0><s5>39</s5></fC07><fC07 i1="03" i2="X" l="SPA"><s0>Sistema nervioso patología</s0><s5>39</s5></fC07><fC07 i1="04" i2="X" l="FRE"><s0>Pathologie de l'encéphale</s0><s5>40</s5></fC07><fC07 i1="04" i2="X" l="ENG"><s0>Cerebral disorder</s0><s5>40</s5></fC07><fC07 i1="04" i2="X" l="SPA"><s0>Encéfalo patología</s0><s5>40</s5></fC07><fC07 i1="05" i2="X" l="FRE"><s0>Syndrome extrapyramidal</s0><s5>41</s5></fC07><fC07 i1="05" i2="X" l="ENG"><s0>Extrapyramidal syndrome</s0><s5>41</s5></fC07><fC07 i1="05" i2="X" l="SPA"><s0>Extrapiramidal síndrome</s0><s5>41</s5></fC07><fC07 i1="06" i2="X" l="FRE"><s0>Pathologie du système nerveux central</s0><s5>42</s5></fC07><fC07 i1="06" i2="X" l="ENG"><s0>Central nervous system disease</s0><s5>42</s5></fC07><fC07 i1="06" i2="X" l="SPA"><s0>Sistema nervosio central patología</s0><s5>42</s5></fC07><fN21><s1>094</s1></fN21><fN44 i1="01"><s1>OTO</s1></fN44><fN82><s1>OTO</s1></fN82></pA></standard><server><NO>PASCAL 11-0143203 INIST</NO><ET>Design and in vitro characterization of PAC1/VPAC1-selective agonists with potent neuroprotective effects</ET><AU>DOAN (Ngoc-Duc); BOURGAULT (Steve); DEJDA (Agnieszka); LETOURNEAU (Myriam); DETHEUX (Michel); VAUDRY (David); VAUDRY (Hubert); CHATENET (David); FOURNIER (Alain)</AU><AF>Institut Armand-Frappier, Institut National de la Recherche Scientifique, Université du Québec, 531 boulevard des Prairies, Ville de Laval/Québec H7V 1B7/Canada (1 aut., 2 aut., 3 aut., 4 aut., 8 aut., 9 aut.); Laboratoire International Associé Samuel de Champlain INSERM - INRS/France/Canada (1 aut., 2 aut., 3 aut., 4 aut., 6 aut., 7 aut., 8 aut., 9 aut.); Euroscreen S.A., 47 Rue Adrienne Bolland/6041 Gosselies/Belgique (5 aut.); INSERM-U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, IFRMP 23, Université de Rouen/76821 Mont-Saint-Aignan/France (6 aut., 7 aut.)</AF><DT>Publication en série; Niveau analytique</DT><SO>Biochemical pharmacology; ISSN 0006-2952; Coden BCPCA6; Pays-Bas; Da. 2011; Vol. 81; No. 4; Pp. 552-561; Bibl. 43 ref.</SO><LA>Anglais</LA><EA>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<sup>7</sup>]PACAP27 and [Hyp<sup>2</sup>]PACAP27 demonstrated their ability to protect potently human dopaminergic SH-SY5Y neuroblasts against the toxicity of MPP<sup>+</sup>, 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.</EA><CC>002B02; 002B17G; 002B17A01</CC><FD>In vitro; Caractérisation; Agoniste; Neuroprotection; Neuroprotecteur; Peptide PACAP; Relation structure activité; Sélectivité; Maladie de Parkinson</FD><FG>Neuropeptide; Maladie dégénérative; Pathologie du système nerveux; Pathologie de l'encéphale; Syndrome extrapyramidal; Pathologie du système nerveux central</FG><ED>In vitro; Characterization; Agonist; Neuroprotection; Neuroprotective agent; Pituitary adenylate cyclase activating peptide; Structure activity relation; Selectivity; Parkinson disease</ED><EG>Neuropeptide; Degenerative disease; Nervous system diseases; Cerebral disorder; Extrapyramidal syndrome; Central nervous system disease</EG><SD>In vitro; Caracterización; Agonista; Neuroprotección; Neuroprotector; Péptido PACAP; Relación estructura actividad; Selectividad; Parkinson enfermedad</SD><LO>INIST-1418.354000193708330100</LO><ID>11-0143203</ID></server></inist></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Canada/explor/ParkinsonCanadaV1/Data/PascalFrancis/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000342 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/PascalFrancis/Corpus/biblio.hfd -nk 000342 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Canada
|area= ParkinsonCanadaV1
|flux= PascalFrancis
|étape= Corpus
|type= RBID
|clé= Pascal:11-0143203
|texte= Design and in vitro characterization of PAC1/VPAC1-selective agonists with potent neuroprotective effects
}}
| This area was generated with Dilib version V0.6.29. |  |