Share This Article:

Potential PET Ligands for Imaging of Cerebral VPAC and PAC Receptors: Are Non-Peptide Small Molecules Superior to Peptide Compounds?

Abstract Full-Text HTML XML Download Download as PDF (Size:793KB) PP. 364-384
DOI: 10.4236/wjns.2015.55036    4,303 Downloads   4,717 Views   Citations
Author(s)    Leave a comment


Pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) have been known for decades to mediate neuroendocrine and vasodilative actions via G-protein-coupled receptors of Class B. These are targets of imaging probes for positron emission tomography (PET) or single photon emission tomography (SPECT) in tumor diagnostics and tumor grading. However, they play only a subordinate role in the development of tracers for brain imaging. Difficulties in development of non-peptide ligands typical for cerebral receptors of PACAP and VIP are shared by all members of Class B receptor family. Essential landmarks have been confirmed for understanding of structural details of Class B receptor molecular signalling during the last five years. High relevance in the explanation of problems in ligand development for these receptors is admitted to the large N-terminal ectodomain markedly different from Class A receptor binding sites and poorly suitable as orthosteric binding sites for the most small-molecule compounds. The present study is focused on the recently available receptor ligands for PAC1, VPAC1 and VPAC2 receptors as well as potential small-molecule lead structures suitable for use in PET or SPECT. Recently, biaryl, cyanothiophene and pentanamide structures with affinities in nM-range have been proposed as non-peptide ligands at VPAC1 and VPAC2 receptors. However, most of these ligands have been classified as non-competitive related to the orthosteric binding site of endogenous peptide ligands of VPAC receptors. For PAC1 receptors have been identified hydrazide compounds for which an inhibitory and potentially competitive mechanism of receptor binding has been postulated based on molecular docking studies.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Pissarek, M. (2015) Potential PET Ligands for Imaging of Cerebral VPAC and PAC Receptors: Are Non-Peptide Small Molecules Superior to Peptide Compounds?. World Journal of Neuroscience, 5, 364-384. doi: 10.4236/wjns.2015.55036.


[1] Said, S.I. and Mutt, V. (1970) Polypeptide with Broad Biological Activity: Isolation from Small Intestine. Science, 169, 1217-1218.
[2] Said, S.I. and Mutt, V. (1972) Isolation from Porcine-Intestinal Wall of a Vasoactive Octacosapeptide Related to Secretin and to Glucagon. European Journal of Biochemistry, 28, 199-204.
[3] Miyata, A., Arimura, A., Dah, R., Minamino, N., Uehara, A., Jiang, L., Culler, M.D. and Coy, D.H. (1989) Isolation of a Novel 38 Residue-Hypothalamic Polypeptide Which Stimulates Adenylate Cyclase in Pituitary Cells. Biochemical and Biophysical Research Communications, 164, 567-574.
[4] Miyata, A., Jiang, L., Dahl, R.D., Kitada, C., Kubo, K., Fujino, M., Minamino, N. and Arimura, A. (1990) Isolation of a Neuropeptide Corresponding to the N-Terminal 27 Residue of the Pituitary Adenylate Cyclase Activating Polypeptide with 38 Residue (PACAP38). Biochemical and Biophysical Research Communications, 170, 643-648.
[5] Harmar, A.J., Arimura, A., Gozes, I., Journot, L., Laburthe, M., Pisegna, J.R., Rawlings, S.R., Robberecht, P., Said, S.I., Sreedharan, S.P., Wank, S.A. and Waschek J.A. (1998) International Union of Pharmacology. VIII Nomenclature of Receptors for Vasoactive Intestinal Peptides and Pituitary Adenylate Cyclase Activating Polypeptide. Pharmacological Reviews, 50, 265-270.
[6] Harmar, A.J., Fahrenkrug, J., Gozes, I., Laburthe, M., May, V., Pisegna, J.R., Vaudry, D., Waschek, J.A. and Said, S.I. (2012) Pharmacology and Functions of Receptors for Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-Activating Polypeptide: IUPHAR Review 1. British Journal of Pharmacology, 166, 4-17.
[7] Harmar, A.J., Marston, H.M., Shen, S., Spratt, C., West, K.M., Sheward, W.J., Morrison, C.F., Dorin, J.R., Piggins, H.D., Reubi, J.C., Kelly, J.S., Maywood, E.S. and Hastings, M.H. (2012) The VPAC2 Receptor Is Essential for Circadian Function in the Mouse Suprachiasmatic Nuclei. Cell, 109, 497-508.
[8] Gonzales, S.M., Kawashima, M., Kamiyoshi, M., Tanaka, K. and Ichinoe, K. (1995) Presence of Vasoactive Intestinal Peptide Receptor in the Hen Hypothalamus. Endocrine Journal, 42, 179-186.
[9] Zawilska, J.B., Niewiadomski, P. and Nowak, J.Z. (2003) PAC1 Receptors in Chick Cerebral Cortex: Characterization by Binding of Pituitary Adenylate Cyclase-Activating Polypeptide, [125I]-PACAP27. Neuroscience Letters, 338, 155-158.
[10] Vaudry, D., Falluel-Morel, A., Bourgault, S., Bassile, M., Burel, D., Wurtz, O., Fournier, A., Chow, B.K.C., Hashimoto, H., Galas, L. and Vaudry, H. (2009) Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery. Pharmacological Reviews, 61, 283-357.
[11] Zaben, M.J. and Gray, W.P. (2013) Neuropeptides and Hippocampal Neurogenesis. Neuropeptides, 47, 431-438.
[12] Castairs, J.R. and Barnes, P.J. (1986) Visualization of Vasoactive Intestinal Peptide Receptors in Human and Guinea Pig Lung. Journal of Pharmacology and Experimental Therapeutics, 239, 249-255.
[13] Diané, A., Payn, G.W. and Gray, S.L. (2014) Multifaces of Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP): From Neuroprotection and Energy Homeostasis to Respiratory and Cardiovascular Systems. Journal of Metabolic Syndrome, 3, 162.
[14] Nakajima, E., Walkup, R.D., Fuji, A., Shearer, T.R. and Azuma, M. (2013) Pituitary Adenylate Cyclase-Activating Peptide Induces Neurite Outgrowth in Cultured Monkey Trigeminal Ganglion Cells: Involvement of Receptor PAC1. Molecular Vision, 19, 174-183.
[15] Delgado, M. and Ganea, D. (2003) Vasoactive Intestinal Peptide Prevents Activated Microglia-Induced Neurodegeneration under Inflammatory Conditions: Potential Therapeutic Role in Brain Trauma. FASEB Journal, 17, 1922-1924.
[16] Tsutsumi, M., Claus, T.H., Liang, Y., Li, Y., Yang, L., Zhu, J., Dela Cruz, F., Peng, X., Chen, H., Yung, S.L., Hamren, S., Livingston, J.N. and Clark, Q.P. (2002) A Potent and Highly Selective VPAC2 Agonist Enhances Glucose-Induced Insulin Release and Glucose Disposal. A Potential Therapy for Type 2 Diabetes. Diabetes, 51, 1453-1460.
[17] Frechilla, D., Garcia-Osta, A., Palacios, S., Cenarruzabeitia, E. and Del Rio, J. (2011) BDNF Mediates the Neuroprotective Effect of PACAP-38 on Rat Cortical Neurons. Neuroreport, 12, 919-923.
[18] Couvineau, A., Ceraudo, E., Tan, Y.-V., Nicole, P. and Laburthe, M. (2012) The VPAC1 Receptor: Structure and Function of a Class B GPCR Prototype. Frontiers in Endocrinology, 3, 139.
[19] Otto, C., Hein, L., Brede, M., Jahns, R., Engelhardt, S., Grone, H.-J. and Schütz, G. (2004) Pulmonary Hypertension and Right Heart Failure in Pituitary Adenylate Cyclase-Activating Polypeptide Type 1 Receptor Deficient Mice. Circulation, 110, 3245-3251.
[20] Faraone, S.V., Skol, A.D., Tsuang, D.W., Young, K.A., Haverstock, S.L., Prabhudesai, S., Mena, F., Menon, A.S., Leong, L., Sautter, F., Baldwin, C., Bingham, S., Weiss, D., Collins, J., Keith, T., Vanden Eng, J.L., Boehnke, M., Tsuang, M.T. and Schellenberg, G.D. (2005) Genome Scan of Schizophrenia Families in a Large Veterans Affairs Cooperative Study Sample: Evidence for Linkage to 18p11.32 and for Racial Heterogeneity on Chromosomes 6 and 14. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 139B, 91-100.
[21] Hashimoto, R., Hashimoto, H., Shintani, N., Chiba, S., Hattori, S., Okada, T., Nakajima, M, Tanaka, K., Kawagishi, N., Nemoto, K., Mori, T., Onishi, T., Noguchi, H., Hori, H., Suzuki, T., Iwata, N., Ozaki, N., Nakabayashi, T., Saitoh, O., Kosuga, A., Tatsumi, M., Kamijima, K., Weinberger, D.R., Kunugi, H. and Baba, A. (2007) Pituitary Adenylate Cyclase Activating Polypeptide Is Associated with Schizophrenia. Molecular Psychiatry, 12, 1026-1032.
[22] Vaudry, D., Gonzalez, B.J., Basille, M., Yon, A., Fournier, A. and Vaudry, H. (2000) Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: From Structure to Functions. Pharmacological Reviews, 52, 269-324.
[23] Kumar, S., Pioszak, A., Zhang, C., Swaminathan, K. and Xu, H.E. (2011) Crystal Structure of the PAC1R Extracellular Domain Unifies a Consensus Fold for Hormone Recognition by Class B G-Protein Coupled Receptors. PLoS ONE, 6, e19682.
[24] Shen, S, Gehlert, D.R. and Collier, D.A. (2013) PACAP and PAC1 Receptor in Brain Development and Behavior. Neuropeptides, 47, 421-430.
[25] Wu, L., Guang, W., Chen, X. and Hong, A. (2014) Homology Modeling and Molecular Docking of Human Pituitary Adenylate Cyclase-Activating Polypeptide I Receptor. Molecular Medicine Reports, 10, 1691-1696.
[26] Dejda, A., Sokolowska, P. and Nowak, J.Z. (2005) Neuroprotective Potential of Three Neuropeptides. Pharmacological Reports, 57, 307-320.
[27] Sullivan, G.M., Parsey, R.V., Kumar, J.S.D., Arango, V., Kassir, S.A., Huang, Y.-Y., Simpson, N.R., van Heertum, R.L. and Mann, J.J. (2007) PET Imaging of CRF1 with [11C]R121919 and [11C]DMP696: Is the Target of Sufficient Density? Nuclear Medicine and Biology, 34, 353-361.
[28] Zorilla, E.P. and Koob, G.F. (2010) Progress in Corticotrophin Releasing Factor 1 Antagonist Development. Drug Discovery Today, 15, 371-383.
[29] Kehne, J.H. and Cain, C.K. (2010) Therapeutic Utility of Non-Peptidic CRF1 Receptor Antagonists in Anxiety, Depression and Stress-Related Disorders: Evidence from Animal Models. Pharmacology & Therapeutics, 128, 460-487.
[30] Hostetler, E.D., Joshi, A.D., Sanabria-Bohorquez, S., Fan, H., Zeng, Z., Purcell, M., Gantert, L., Riffel, K., William, M., O’Malley, S., Miller, P., Selnick, H.G., Gallicchio, S.N., Bell, I.M., Salvatore, C., Kane, S.A., Li, C.C., Hargreaves, R., de Groot, T., Bormans, G., van Hecken, A., Derdelinckx, I., de Hoon, J., Reynders, T., Declercq, R., de Lepeleire, I., Kennedy, W.D., Blanchard, R., Marcantonio, E.E., Sur, C., Cook, J.J., van Laere, K. and Evelhoch, J.L. (2013) In Vivo Quantification of Calcitonin Gene-Related Peptide Receptor Occupancy by Telcagepant in Rhesus Monkey and Human Brain Using the Positron Emission Tomography Tracer [11C]MK-4232. Journal of Pharmacology and Experimental Pharmaceutics, 347, 478-486.
[31] Shoichet, B.K. and Kobilka, B.K. (2012) Structure-Based Drug Screening for G-Protein-Coupled Receptors. Trends in Pharmacological Sciences, 33, 268-272.
[32] Hausch, F. (2013) Structures of Class B G Protein-Coupled Receptors: Prospects for Drug Discovery. Angewandte Chemie International Edition, 52, 12783-12785.
[33] Hollenstein, K., Kean, J., Bortolato, A., Cheng, R.K.Y., Dore, A.S., Jazayeri, A., Cooke, R.M., Weir, M. and Marshall, F.H. (2013) Structure of Class B GPCR Corticotropin Releasing Factor Receptor 1. Nature, 499, 438-443.
[34] Siu, F.Y., de Graaf, C., Han, G.W., Yang, D., Zhang, Z., Zhou, C., Xu, Q., Wacker, D., Joseph, J.S., Liu, W., Lau, J., Cherezov, V., Katritch, V., Wang, M.-W. and Stevens, R.C. (2013) Structure of the Human Glucagon Class B G-Protein-Coupled Receptor. Nature, 499, 444-451.
[35] Siu, F.Y. and Stevens, R.C. (2010) RAMP-ing up Class B GPCR ECD Structural Coverage. Structure, 18, 1067-1068.
[36] Hollenstein, K., de Graaf, C., Bortolato, A., Wang, M.-W., Marshall, F.H. and Stevens, R.C. (2014) Insights into Structure of Class B GPCRs. Trends in Pharmacological Sciences, 35, 12-22.
[37] Bortolato, A., Dore, A.S., Hollenstein, K., Tehan, B.G., Mason, J.S. and Marshall, F.H. (2014) Structure of Class B GPCRS: New Horizons for Drug Discovery. British Journal of Pharmacology, 171, 3132-3145.
[38] Wootten, D., Lindmark, H., Kadmiel, M., Willcockson, H., Caron, K.M., Barwell, J., Drmota, T. and Poyner, D.R. (2013) Receptor Activity Modifying Proteins (RAMPS) Interact with the VPAC2 Receptor and CRF1 Receptors and Modulate Their Function. British Journal of Pharmacology, 168, 822-834.
[39] Archbold, J.K., Flanagan, J.U., Watkins, H.A., Gingell, J.J. and Hay, D.L. (2011) Structural Insights into RAMP Modification of Secretin Family G Protein-Coupled Receptors: Implications for Drug Development. Trends in Pharmacological Sciences, 32, 591-600.
[40] Christopoulos, A., Christopoulos, G., Morfis, M., Udawela, M., Laburthe, M., Couvineau, A., Kuwasako, K., Tilakaratne, N. and Sexton, P.M. (2003) Novel Receptor Partners and Function of Receptor Activity-Modifying Proteins. Journal of Biological Chemistry, 278, 3293-3297.
[41] Roux, B.T. and Cottrell, G.S. (2014) G Protein-Coupled Receptors: What a Difference a “Partner” Makes. International Journal of Molecular Sciences, 15, 1112-1142.
[42] Foord, S.M. and Marshall, F.H. (1999) RAMPS: Accessory Proteins for Seven Transmembrane Domain Receptors. Trends in Pharmacological Sciences, 20, 184-187.
[43] Moore, E.L., Gingell, J.J., Kane, S.A., Hay, D.L. and Salvatore, C.A. (2010) Mapping the CGRP Receptor Ligand Binding Domain: Tryptophan-84 of RAMP1 Is Critical for Agonist and Antagonist Binding. Biochemical and Biophysical Research Communications, 394, 141-145.
[44] Schottelius, M. and Wester, H.-J. (2009) Molecular Imaging Targeting Peptide Receptors. Methods, 48, 161-177.
[45] Fani, M., Maecke, H.R. and Okarvi, S.M. (2012) Radiolabelled Peptides: Valuable Tools for the Detection and Treatment of Cancer. Theranostics, 2, 481-501.
[46] Beebe, X., Darzak, D., Rachel, A., Davis-Taber, R.A., Uchic, M.E., Scott, V.E., Jarvis, M.F. and Stewart, A.O. (2008) Discovery and SAR of Hydrazide Antagonists of the Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Receptor Type 1 (PAC1-R). Bioorganic and Medicinal Chemical Letters, 18, 2162-2166.
[47] Chu, A., Caldwel, J.S. and Chen, Y.C. (2010) Identification and Characterization of a Small Molecule Antagonist of Human VPAC2 Receptor. Molecular Pharmacology, 77, 95-101.
[48] Neumann, J.M., Couvineau, A., Murail, S., Lacapère, J.J., Jamin, N. and Laburthe, M. (2008) Class-B GPCR Activation: Is Ligand Helix-Capping the Key? Trends in Biochemical Sciences, 33, 314-319.
[49] Watkins, H.A., Au, M. and Hay, D.L. (2012) The Structure of Secretin Family GPCR Peptide Ligands: Implications for Receptor Pharmacology and Drug Development. Drug Discovery Today, 17, 1006-1014.
[50] Lee, E.H. and Seo, S.R. (2014) Neuroprotective Roles of Pituitary Adenylate Cyclase-Activating Polypeptide in Neurodegenerative Diseases. BMB Reports, 47, 369-375.
[51] Mayo, K.E., Miller, L.J., Bataille, D., Dalle, S., Goke, B., Thorens, B. and Drucker, D.J. (2003) International Union of Pharmacology: XXXV. The Glucagon Receptor Family. Pharmacological Reviews, 55, 165-194.
[52] Will-Shahab, L., Wallukat, G. and Küttner, I. (1992) G Protein-Coupled PACAP Receptors in Cardiac Sarcolemmal Membranes. Journal of Molecular Cellular Cardiology, 24, S22.
[53] Scaldaffieri, M.L., Modesti, A., Palumbo, C., Ulisse, S., Fabbri, A., Picione, E., Frajese, G. and Moretti, C. (2000) Pituitary Adenylate Cyclase Activating Polypeptide and PACAP-Receptor Type 1 Expression in Rat and Human Placenta. Endocrinology, 141, 1158-1167.
[54] Colwell, C.S., Michel, S., Itri, J., Rodriguez, W., Tam, J., Lelievre, V., Hu, Z. and Waschek, J.A. (2004) Selective Deficits in the Circadian Light Response in Mice Lacking PACAP. American Journal of Physiology, Regulatory, Integrative and Comparative Physiology, 287, 1194-1201.
[55] Pantazopoulos, H., Dolatshad, H. and Davis, F.C. (2010) Chronic Stimulation of the Hypothalamic Vasoactive Intestinal Peptide Receptor Lengthen Circadian Period in Mice and Hamsters. American Journal of Physiology, Regulatory, Integrative and Comparative Physiology, 299, R379-R385.
[56] Girard, B.A., Lelievre, V., Braas, K.M., Razinia, T., Vizzard, M.A., Ioffe, Y., El Meskini, R., Ronnett, G.V., Waschek, J.A. and May, V. (2006) Noncompensation in Peptide/Receptor Gene Expression and Distinct Behavioral Phenotypes in VIP and PACAP Deficient Mice. Journal of Neurochemistry, 99, 499-513.
[57] Jaworski, D.M. and Proctor, M.D. (2000) Developmental Regulation of Pituitary Adenylate Cyclase-Activating Polypeptide and PAC1 Receptor mRNA Expression in the Rat Central Nervous System. Developmental Brain Research, 120, 27-39.
[58] Sun, C., Song, D., Davis-Taber, R.A., Barrett, L.W., Scott, V.E., Richardson, P.L., Pereda-Lopez, A., Uchic, M.E., Solomon, L.R., Lake, M.R., Walter, K.A., Hajduk, P.J. and Olejniczak, E.T. (2007) Solution Structure and Mutational Analysis of Pituitary Adenylate Cyclase-Activating Polypeptide Binding to the Extracellular Domain of PAC1-Rs. Proceedings of the National Academy of Sciences, 104, 7875-7880.
[59] Nicole, P., Lins, L., Rouyer-Fessard, C., Drouot, C., Fulcrand, P., Thomas, A., Couvineau, A., Martinez, J., Brasseur, R. and Laburthe, M. (2000) Identification of Key Residue for Interaction of Vasoactive Intestina Peptide with Human VPAC1 and VPAC2 Receptors and Development of Highly Selective VPAC1 Receptor Agonist. Journal of Biological Chemistry, 275, 24003-24012.
[60] Igarashi, H., Ito, T., Pradhan, T.K., Mantey, S.A., Hou, W., Coy, D.H. and Jensen R.T. (2002) Elucidation of the Vasoactive Intestinal Peptide Pharmacophore for VPAC2 Receptors in Human and Rat Comparison to the Pharmacophore for VPAC1 Receptors. Journal of Pharmacology and Experimental Therapeutics, 303, 445-460.
[61] Laburthe, M., Couvineau, A. and Marie, J.C. (2002) Molecular Pharmacology and Structure of VPAC Receptors for VIP and PACAP. Receptor Channels, 108, 137-153.
[62] Igarashi, H., Ito, T., Mantey, S.A., Pradhan, T.K., Hou, W., Coy, D.H. and Jensen, R.T. (2005) Development of Simplified Vasoactive Intestinal Peptide Analogs with Receptor Selectivity and Stability for Human Vasoactive Intestinal Peptide/Pituitary Adenylate Cyclase-Activating Polypeptide Receptors. Journal of Pharmacology and Experimental Therapeutics, 315, 370-381.
[63] Dickson, L. and Finlayson, K. (2009) VPAC and PAC Receptors: From Ligands to Function. Pharmacology & Therapeutics, 121, 294-316.
[64] Yadav, M., Huang, M.-C. and Goetzl, E.J. (2011) VPAC1 (Vasoactive Intestinal Peptide (VIP) Receptor Type 1) G Protein Coupled Receptor Mediation of VIP Enhancement of Murine Experimental Colitis. Cellular Immunology, 267, 124-132.
[65] Ma, B.-Q., Zhang, M. and Ba, L. (2015) Plasma Pituitary Adenylate Cyclase-Activating Polypeptide Concentrations and Mortality after Acute Spontaneous Basal Ganglia Hemorrhage. Clinica Chimica Acta, 439, 102-106.
[66] Lin, C.-H., Chiu, L., Lee, H.-T., Chiang, C.-W., Liu, S.-P., Hsu, Y.-H., Lin, S.-Z., Hsu, C.-Y., Hsieh, C.-H. and Shyu, W.-C. (2015) PACAP38/PAC1 Signaling Induces Bone Marrow-Derived Cells Homing to Ischemic Brain. Stem Cells, 33, 1153-1172.
[67] Ressler, K.J., Mercer, K.B., Bradley, B., Jovanovic, T., Mahan, A., Kerley, K., Norrholm, S.D., Kilaru, V., Smith, A.K., Myers, A.J., Ramirez, M., Engel, A., Hammack, S.E., Toufexis, D., Braas, K.M., Binder, E.B. and May, V. (2011) Post-Traumatic Stress Disorder Is Associated with PACAP and PAC1 Receptor. Nature, 470, 492-497.
[68] Igarashi, H., Fujimori, N., Ito, T., Nakamura, T., Oono, T., Nakamura, K., Suzuki, K., Jensen, R.T. and Takayanagi, R. (2011) Vasoactive Intestinal Peptide (VIP) Receptor-Elucidation of Structure and Function for Therapeutic Applications. International Journal of Clinical Medicine, 2, 500-508.
[69] Baranowska, B., Radzikowska, M., Wasilewska-Dziubinska, E., Roguski, K. and Borowiec, M. (2000) Disturbed Release of Gastrointestinal Peptides in Anorexia Nervosa and Obesity. Diabetes, Obesity and Metabolism, 2, 99-103.
[70] Ohtaki, H., Nakamachi, T., Dogi, K., Aizawa, Y., Takaki, A., Hodoyama, K., Yofu, S., Hashimoto, H., Shintani, N., Baba, A., Kopf, M., Iwakura, M., Arimura, A. and Shioda, S. (2006) Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Decreases Ischemic Neuronal Cell Death in Association with IL-6. Proceedings of the National Academy of Sciences, 103, 7488-7493.
[71] O’Donnell, M., Garippa, R.J., Rinaldi, N., Selig, W.M., Simko, B., Renzetti, L., Tannu, S.A., Wassermann, M.A., Welton, A. and Bolin, D.R. (1994) Ro 25-1553: A Novel, Long-Acting Vasoactive Intestinal Peptide Agonist. Part I: In Vitro and in Vivo Bronchodilator Studies. Journal of Pharmacology and Experimental Therapeutics, 270, 1282-1288.
[72] O’Donnell, M., Garippa, R.J., Rinald, I.N., Selig, W.M., Tocker, J.E., Tannu, S.A., Wasserman, M.A., Welton, A. and Bolin, D.R. (1994) RO 25-1553: A Novel, Long-Acting Vasoactive Intestinal Peptide Agonist. Part II: Effect on in Vitro and in Vivo Models of Pulmonary Anaphylaxis. Journal of Pharmacology and Experimental Therapeutics, 270, 1289-1294.
[73] Leroux, P., Vaudry, H., Fournier, A., St-Pierre, S. and Pelletier, G. (1984) Characterization and Localization of Vasoactive Intestinal Peptide Receptors in the Rat Lung. Endocrinology, 114, 1506-1512.
[74] Polak, J.M. and Bloom, S.R. (1982) Occurrence and Distribution of Regulatory Peptides in the Respiratory Tract. Experimental Lung Research, 3, 313-328.
[75] Hashimoto, H., Shintani, N., Nishino, A., Okabe, M., Ikawa, M., Matsuyama, S., Itoh, K., Yamamoto, K., Tomimoto, S., Fujit, A.T., Hagihara, N., Mori, W., Koyama, Y., Matsuda, T., Nagata, S. and Baba, A. (2000) Mice with Markedly Reduced PACAP (PAC1) Receptor Expression by Targeted Deletion of the Signal Peptide. Journal of Neurochemistry, 75, 1810-1817.
[76] Zawilska, J.B., Dejda, A., Niewiadomski, P., Gozes, I. and Nowak, J.Z. (2005) Receptors for VIP and PACAP in Guinea Pig Cerebral Cortex. Effects on Cyclic AMP Synthesis and Characterization by 125I-VIP Binding. Journal of Molecular Neuroscience, 25, 215-224.
[77] Joo, K.M., Chung, Y.H., Kim, M.K., Nam, R.H., Lee, B.L. and Cha, C.I. (2004) Distribution of Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-Activating Polypeptide Receptors (VPAC1, VPAC2 , and PAC1 Receptor) in the Rat Brain. Journal of Comparative Neurology, 476, 388-413.
[78] Cuha-Reis, D., Ribeiro, J.A. and Sebastiao, A.M. (2005) VIP Enhances Synaptic Transmission to Hippocampal CA1 Pyramidal Cells through Activation of both VPAC1 and VPAC2 Receptors. Brain Research, 1049, 52-60.
[79] Blechman, J. and Levkowitz, G. (2013) Alternative Splicing of the Pituitary Adenylate Cyclase-Activating Polypeptide Receptor PAC1: Mechanism of Fine Tuning of Brain Activity. Frontiers in Endocrinology, 4, 1-19.
[80] Lang, B., Song, B., Davidson, W., MacKenzie, A., Smith, N., McCaig, C.D., Harmar, A.J. and Shen, S. (2006) Expression of the Human PAC1 Receptor Leads to Dose-Dependent Hydrocephalus-Related Abnormalities in Mice. Journal of Clinical Investigations, 116, 1924-1934.
[81] Sun, Q.-Q., Prince, D.A. and Huguenard, J.R. (2003) Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase Activating Polypeptide Activate Hyperpolarization Activated Cation Current and Depolarize Thalamocortical Neurons in Vitro. Journal of Neuroscience, 23, 2751-2758.
[82] Hoshino, M., Yanihara, C., Hong, Y.-M., Kishida, S., Katsumaru, Y., Vandermeers, A., Vandermeers-Piret, M.-C., Robberecht, P., Christophe, J. and Yanaihara, N. (1984) Primary Structure of Helodermin, a VIP-Secretin-Like Peptide Isolated from Gila Monster Venom. FEBS Letters, 178, 233-239.
[83] Robberecht, P., Waelbroeck, M., Camus, J.C., DeNeef, P., Coy, D.H. and Christophe, J. (1984) Effect of His1 Modifications on the Ability of Vasoactive Intestinal Peptide to Stimulate Adenylate Cyclase from Rat and Human Tissue. Peptides, 5, 529-535.
[84] Laburthe, M., Couvineau, A. and Tan, V. (2007) Class II G Protein-Coupled Receptors for VIP and PACAP Structure, Models of Activation and Pharmacology. Peptides, 28, 1631-1639.
[85] Hoare, S.R.J. (2005) Mechanisms of Peptide and Nonpeptide Ligand Binding to Class B G-Protein Coupled Receptors. Drug Discovery Today, 10, 417-427.
[86] Dong, M., Pinon, D.I., Asmann, Y.W. and Miller, L.J. (2006) Possible Endogenous Agonist Mechanism for Activation of Secretin Family G-Protein-Coupled Receptors. Molecular Pharmacology, 70, 206-213.
[87] terHaar, E., Koth, C.M., Abdul-Manan, N., Swenson, L., Coll, J.T., Lippke, J.A., Lepre, C.A., Garcia-Guzman, M. and Moore, J.M. (2010) Crystal Structure of the Ectodomain Complex of the CGRP Receptor, a Class B GPCR, Reveals the Site of Drug Antagonism. Structure, 18, 1083-1093.
[88] Parthier, C., Reedtz-Runge, S., Rudolph, R. and Stubbs, M.T. (2009) Passing the Baton in Class B GPCRs: Peptide Hormone Activation via Helix Induction. Trends in Biochemical Sciences, 34, 303-310.
[89] Usdin, T.B., Bonner, T.I. and Mezey, E. (1994) Two Receptors for Vasoactive Intestinal Polypeptide with Similar Specificity and Complementary Distributions. Endocrinology, 135, 2662-2680.
[90] Harikrishnan, L.S., Srivastava, N., Kayser, L.E., Nirschl, D.S., Kumaragurubaran, K., Roy, A., Gupta, A., Karmakar, S., Karatt, T., Mathur, A., Burford, N.T., Chen, J., Kong, Y., Cvijic, M.E., Coope, C.B., Poss, M.A., Trainor, G.L. and Wong, T.W. (2012) Identification and Optimization of Small Molecule Antagonists of Vasoactive Intestinal Peptide Receptor-1 (VIPR1). Bioorganic and Medicinal Chemistry Letters, 22, 2287-2290.
[91] Dockray, G.J. (1994) Vasoactive Intestinal Polypeptide and Related Peptides. In: Walsh, J.H. and Dockray, G.J., Eds., Gut Peptides, Raven Press Ltd., New York, 447-472.
[92] Inagaki, N., Yoshida, H., Mizuta, M., Fujii, Y., Gonol, T., Mijazaki, J. and Seino, S. (1994) Cloning and Functional Characterization of a Third Pituitary Adenylate Cyclase Activating Polypeptide Receptor Subtype Expressed in Insulin Secreting Cells. Proceedings of the National Academy of Sciences, 91, 2679-2683.
[93] Sekiguchi, Y., Kasai, K., Hasegawa, K., Suzuki, Y. and Shimoda, S. (1994) Glycogenolytic Activity of Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) in Vivo and in Vitro. Life Science, 55, 1219-1228.
[94] Yokota, C., Kawai, K., Ohashi, S., Watanabe, Y. and Yamashita, K. (1995) PACAP Stimulates Glucose Output from the Perfused Rat liver. Peptides, 16, 55-60.
[95] Wei, Y. and Mojsov, S. (1996) Multiple Human Receptors for Pituitary Adenylate Cyclase Activating Polypeptide and Vasoactive Intestinal Peptide Are Expressed in Tissue-Specific Manner. Annals of the New York Academy of Sciences, 805, 624-627.
[96] Yu, R.J., Zhang, H.H., Huang, L., Liu, X.F. and Chen, J.S. (2011) Anti-Hyperglycemic, Antioxidant and Anti-Inflammatory Effects of VIP and a VPAC1 Agonist on Streptozotocin-Induced Diabetic Mice. Peptides, 32, 216-222.
[97] Ago, Y., Condro, M.C., Tan, Y.-V., Ghiani, C.A., Colwell, C.S., Cushman, J.D., Fanselow, M.S., Hashimoto, H. and Waschek, J.A. (2015) Reductions in Synaptic Proteins and Selective Alteration of Prepulse Inhibition in Male C57BL/6 Mice after Postnatal Administration of a VIP Receptor (VIPR2) Agonist. Psychopharmacology, 232, 2181-2189.
[98] Asnicar, M.A., Koster, A., Heiman, M.L., Tinsley, F., Smith, D.P., Galbreath, E., Fox, N., Ma, Y.L. and Blum, W.F. (2002) Vasoactive Intestinal Polypeptide/Pituitary Adenylate Cyclase-Activating Peptide Receptor 2 Deficiency in Mice Results in Growth Retardation and Increased Basal Metabolic Rate. Endocrinology, 143, 3994-4006.
[99] Nicot, A., Otto, T., Brabet, P. and DiCicco-Bloom, M. (2004) Altered Social Behavior in Pituitary Adenylate Cyclase-Activating Type 1 Receptor-Deficient Mice. Journal of Neuroscience, 24, 8786-8795.
[100] Otto, C., Martin, M., Wolfer, D.P., Lipp, H.-P., Maldonado, R. and Schütz, G. (2001) Altered Emotional Behavior in PACAP-Type—I-Receptor-Deficient Mice. Molecular Brain Research, 92, 78-84.
[101] Moreno, D., Gourlet, P., De Neef, P., Cnudde, J., Waelbroeck, M. and Robberecht, P. (2000) Development of Selective Agonists and Antagonists for the Human Vasoactive Intestinal Polypeptide VPAC2 Receptor. Peptides, 21, 1543-1549.
[102] Gourlet, P., Vertongen, P., Vandermeers, A., Vandermeers-Piret, M.-C., Rathe, J., de Neef, P., Waelbroeck, M. and Robberecht P. (1997) The Long-Acting Vasoactive Intestinal Polypeptide Agonist Ro 25-1553 Is Highly Selective of the VIP2 Receptor Subclass. Peptides, 18, 403-408.
[103] Ceraudo, E., Tan, Y.-V., Nicole, P., Couvineau, A. and Laburthe, M. (2008) The N-Terminal Parts of VIP and Antagonist PG97-269 Physically Interact with Different Regions of the Human VPAC1 Receptor. Journal of Molecular Neurosciences, 36, 245-248.
[104] Boni, L.J., Ploug, K.B., Jansen-Olensen, J. and Gupta, S. (2009) The in Vivo Effect of VIP, PACAP-38 and PACAP-27 and mRNA Expression of Their Receptors in Rat Middle Meningeal Artery. Cephalagia, 29, 837-847.
[105] Dickson, L., Aramori, I., McCulloch, J., Sharkey, J. and Finlayson, K. (2006) A Systematic Comparison of Intracellular Cyclic AMP and Calcium Signaling Highlights Complexities in Human VPAC/PAC Receptor Pharmacology. Neuropharmacology, 51, 1086-1098.
[106] Pan, C.Q., Li, F., Tom, I., Wang, W., Dumas, M., Froland, W., Yung, S.L., Li, Y., Roczniak, S., Claus, T.H., Wang, C.Y. and Whelan, J.P. (2007) Engineering Novel VPAC2-Selective Agonists with Improved Stability and Glucose-Lowering Activity in Vivo. Journal of Pharmacology and Experimental Therapeutics, 320, 900-906.
[107] Xia, M., Sreedharan, S.P., Bolin, D.R., Gaufo, G.O. and Goetzl, E.J. (1997) Novel Cyclic Peptide Agonist of High Potency and Selectivity for the Type II Vasoactive Intestinal Peptide Receptor. Journal of Pharmacology and Experimental Therapeutics, 281, 629-633.
[108] Vertongen, P., Schiffmann, S.N., Gourlet, P. and Robberecht, P. (1997) Autoradiographic Visualization of the Receptor Subclasses for Vasoactive Intestinal Polypeptide. Peptides, 18, 1547-1554.
[109] Uchida, D., Tatsuno, I., Tanaka, T., Hirai, A., Saito, Y., Moro, O. and Tajima, M. (1998) Maxadilan Is a Specific Agonist and Its Deleted Peptide (M65) Is a Specific Antagonist for PACAP Type 1 Receptor. Annals of the New York Academy of Sciences, 865, 253-258.
[110] Lerner, E.A., Iuga, A.O. and Reddy, V.B. (2007) Maxadilan, a PAC1 Agonist from Sand Flies. Peptides, 28, 1651-1654.
[111] Lerner, E.A. and Shoemaker, C.B. (1992) Maxadilan: Cloning and Functional Expression of the Gene Encoding This Potent Vasodilator Peptide. Journal of Biological Chemistry, 267, 1062-1066.
[112] Hadwen, J., MacKenzie, D., Shamim, F., Mongeon, K., Holcik, M., MacKenzie, A. and Faroq, F. (2014) VPAC2 Receptor Agonist BAY 55-9837 Increases SMN Protein Levels and Moderates Disease Phenotype in Severe Spinal Muscular Atrophy Mouse Models. Orphanet Journal of Rare Diseases, 9, 4.
[113] Sugarman, E.A., Nagan, N., Zhu, H., Akmaev, V.R., Zhou, Z., Rohlfs, E.M., Flynn, K., Hendrickson, B.C., Scholl, T., Sirko-Osada, D.A. and Allitto, B.A. (2012) Pan-Ethnic Carrier Screening and Prenatal Diagnosis for Spinal Muscular Atrophy: Clinical Laboratory Analysis of >72400 Specimens. European Journal of Genetics, 20, 27-32.
[114] Lindén, A., Hansson, L., Andersson, A., Palmqvist, M., Arvidsson, P., Lofdahl, C.-G. and Larsson, P. (2003) Bronchodilation by an Inhaled VPAC2 Receptor Agonist in Patients with Stable Asthma. Thorax, 58, 217-221.
[115] Moro, O. and Lerner, E.A. (1997) Maxadilan, the Vasodilator from Sand Flies, Is a Specific Pituitary Adenylate Cyclase Activating Peptide Type I Receptor Agonist. Journal of Biological Chemistry, 272, 966-970.
[116] Svensjo, E., Saraiva, E.M., Bozza, M.T., Oliveira, S.M.P., Lerner, E.A. and Scharfstein, J. (2009) Salivary Gland Homogenates of Lutzomyia longipalpis and Its Vasodilatory Peptide Maxadilan Cause Plasma Leakage via PAC1 Receptor Activation. Journal of Vascular Research, 46, 435-446.
[117] Hoare, S.R.J. (2007) Allosteric Modulators of Class B G Protein-Coupled Receptors. Current Neuropharmacology, 5, 168-179.
[118] Pissarek, M. (2014) Neuropeptide Receptors in Pain Circuitries: Useful Targets for CNS Imaging with Non-Peptide Ligands Suitable for PET? World Journal of Neuroscience, 4, 353-383.
[119] Dong, M., Pinon, D.I. and Miller, L.J. (2008) Exploration of the Endogenous Agonist Mechanism for Activation of Secretin and VPAC1 Receptors Using Synthetic Glycosylated Peptides. Journal of Molecular Neuroscience, 36, 254-259.
[120] Robl, J.A. (1990) A New and Versatile Route for the Synthesis of Highly Substituted Benzenoids. Tetrahedron Letters, 31, 3421-3424.
[121] Madsen, P., Ling, A., Plewe, M., Sams, C.K., Knudsen, L.B., Sidelmann, U.G., Ynddal, L., Brand, C.L., Andersen, B., Murphy, D., Teng, M., Truesdale, L., Kiel, D., May, J., Kuki, A., Shi, S.H., Johnson, M.D., Teston, K., Feng, J., Lakis, J., Anderes, K., Gregor, V. and Lau, J. (2002) Optimization of Alkylidene Hydrazide Based Human Glucagon Receptor Antagonists. Discovery of the Highly Potent and Orally Available 3-Cyano-4-Hydroxybenzoic Acid [1-(2,3,5,6-teramethylbenzyl)-1H-indol-4-ylmethylene] Hydrazide. Journal of Medicinal Chemistry, 45, 5755-5775.
[122] Yu, R., Guo, X., Zhong, J., Li, M., Zeng, Z. and Zhang, H. (2012) The N-Terminal HSDCIF Is Required for Cell Surface Trafficking and Dimerization of Family B G Protein Coupled Receptor PAC1. PLoS ONE, 7, e51811.
[123] Jagoda, E.M., Lang, L., McCullough, K., Contoreggi, C., Moon, K.B., Ma, Y., Rice, K.C., Szajek, L.P., Eckelman, W.C. and Kiesewetter, D.O. (2011) [76Br]BMK-152, a Nonpeptide Analogue, with High Affinity and Low Nonspecific Binding for the Corticotrophin-Releasing Factor Type 1 Receptor. Synapse, 65, 910-918.
[124] Zuev, D., Mattson, R.J., Huang, H., Mattson, G.K., Zueva, L., Nielsen, M., Kozlowski, E.S., Huang, X.S., Dedong, W., Gao, Q., Lodge, N.J., Bronson, J.J. and Macor, J.E. (2011) Potential CRF1R PET Imaging Agents: N-Flu-oroalkyl-8-(6-methoxy-2-methyl-pyridin-3-yl)-2,7-dime-thyl-N-alkylpyrazolo[1,5-a][1,3,5]triazin-4-amines. Bioorganic & Medicinal Chemistry Letters, 21, 2484-2488.
[125] Chugunov, A.O., Simms, J., Poyner, D.R., Dehouck, Y., Rooman, M., Gilis, D. and Langer, I. (2010) Evidence That Interaction between Conserved Residues in Transmembrane Helices 2,3 and 7 Are Crucial for Human VPAC 1 Receptor Activation. Molecular Pharmacology, 78, 394-401.
[126] Langer, I. (2012) Conformational Switches in the VPAC1 Receptor. British Journal of Pharmacology, 166, 79-84.
[127] Dong, M., Xu, X., Ball, A.M., Makhoul, J.A., Lam, P.C.H., Pinon, D.I., Orry, A., Sexton, P.M., Abagyan, R. and Miller, L.J. (2012) Mapping Spatial Approximations between the Amino Terminus of Secretin and Each of the Extracellular Loops of Its Receptor Using Cysteine Trapping. FASEB Journal, 26, 5092-5105.
[128] Katritch, V., Cherezov, V. and Stevens, R.C. (2012) Diversity and Modularity of G Protein-Coupled Receptor Structures. Trends in Pharmacological Sciences, 33, 17-26.
[129] Unal, H. and Karnik, S.S. (2012) Domain Coupling in GPCRs: The Engine for Induced Conformational Changes. Trends in Pharmacological Sciences, 33, 79-88.
[130] Avlani, V.A., Gregory, K.J., Morton, C.J., Parker, M.W., Sexton, P.M. and Christopoulos, A. (2007) Critical Role for the Second Extracellular Loop in the Binding of Both Orthosteric and Allosteric G Protein-Coupled Receptor Ligands. Journal of Biological Chemistry, 282, 25677-25686.
[131] Solano, R.M., Langer, I., Perret, J., Vertongen, P., Juarranz, M.G., Robberecht, P. and Waelbroeck, M. (2001) Two Basic Residues of the H-VPAC1 Receptor Second Transmembrane Helix Are Essential for Ligand Binding and Signal Transduction. Journal of Biological Chemistry, 276, 1084-1088.
[132] Donelly, D. (2012) The Structure and Function of the Glucagon-Like Peptide-1 Receptor and Its Ligands. British Journal of Pharmacology, 166, 27-41.
[133] Lagerstrom, M.C. and Schioth, H.B. (2008) Structural Diversity of G Protein-Coupled Receptors and Significance for Drug Discovery. Nature Reviews, 7, 339-357.
[134] Mustafa, T. and Eiden, L.E. (2006) Secretin Superfamily: PACAP, VIP and Related Neuropeptides In: Lajtha, A. and Lim, R., Eds., Handbook of Neurochemistry and Neurobiology: Neuroactive Proteins and Peptides, 3rd Edition, Springer-Verlag, Berlin, 476.

comments powered by Disqus

Copyright © 2019 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.