Neuropeptide Receptors in Pain Circuitries: Useful Targets for CNS Imaging with Non-Peptide Ligands Suitable for PET?

Pissarek, Margit

doi:10.4236/wjns.2014.44040

Cited by 1 publication

(1 citation statement)

References 224 publications

(222 reference statements)

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“…However, these compounds have been discussed rather as allosteric modulators than as drugs docking orthosterically and acting competitively [117]. Also for the CGRP receptor ligand MK4232, described 2013 by Hostetler et al [30], in first successful PET experiments binding modalities in the brain let open questions even if the compound was bound to the parts of the brain in a manner reflecting the regions typically showing high densities of the receptor [118]. The involvement of non-peptide ligands at VPAC and PAC receptors might extend the spectrum of tracers contributing to the characterization of functional basis of mental diseases and of responses to therapeutic interventions in neurological disorders.…”

Section: Non-peptide Ligands Of Vpac and Pac Receptorsmentioning

confidence: 99%

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

Pissarek¹

2015

WJNS

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Pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) have been known for decades to mediate neuroendocrine and vasodilative actions via G-proteincoupled 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. M. Pissarek 365

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Section: Non-peptide Ligands Of Vpac and Pac Receptorsmentioning

confidence: 99%