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Pharmacological MRI as a Molecular Imaging Technique
Published in Michel M. J. Modo, Jeff W. M. Bulte, Molecular and Cellular MR Imaging, 2007
Y. Iris Chen, Bruce G. Jenkins
Indeed, phMRI with an A2A antagonist 3,7-dimethyl-1-propargylaxanthine (DMPX) challenge induced rCBV decrease in CPu and NAc, the areas with a dense population of A2A receptor (Figure 12.7),88 similar to the rCBV changes induced by a D2 agonist.71 The effect of the A2A antagonist on the dopaminergic function can be investigated by DMPX post-treatment on AMPH pretreatment animals (20-min gap between the two treatments). Post-treatment of DMPX attenuated the AMPH-induced rCBV increase in the A2A receptor populated areas and also in thalamus, cingulate cortex, and frontal cortex — areas not populated with A2A receptors, but downstream structures along the basal ganglia circuitry.88 The DMPX-induced rCBV modulation in CPu was parallel to the microdialysis measurement of DA release but disassociated with the global cardiac and respiratory function.88
Approaches for designing and discovering purinergic drugs for gastrointestinal diseases
Published in Expert Opinion on Drug Discovery, 2020
Diego Dal Ben, Luca Antonioli, Catia Lambertucci, Andrea Spinaci, Matteo Fornai, Vanessa D’Antongiovanni, Carolina Pellegrini, Corrado Blandizzi, Rosaria Volpini
A relevant number of potent and subtype selective AR ligands have been developed to date [66–70]. A key modification of the endogenous agonist Ado was made at the 5ʹ-position of the sugar with the insertion of an alkylcarboxamido group, to obtain the so-called NECA (N-ethylcarboxamidoAdo, Figure 3) or MECA (N-methylcarboxamidoAdo). NECA is a nonselective standard AR agonist. Generally, the AR agonists are Ado or NECA/MECA derivatives, presenting various substituents in the 2- or N6-position of the purine core and/or additional modifications at the ribose ring. In the N6-position of the nucleoside, the A1AR agonists often present a cycloalkyl group (i.e. CPA, CCPA, CHA, Figure 3), while the A3AR agonists present small alkyl groups or an iodobenzyl substituent (IB-MECA or Cl-IB-MECA, Figure 3) and the A2AAR agonists generally present an unsubstituted 6-amine. At the 2-position, the A1AR agonists often are unsubstituted or present small groups, while the A2AAR agonists generally bear large substituents with a mix of polar and nonpolar functional groups (i.e. ATL-146e or CGS21680, Figure 3). Among these compounds is regadenoson, clinically used as coronary vasodilator. The most selective A3AR agonists may present a 2-halogen atom or 2-arylalkynyl substituents. In the last years, non-nucleoside agonists of the ARs were reported (i.e. capadenoson, Figure 3), generally endowed with A1AR selectivity [71], even if selective A2AAR and A2BAR (i.e. BAY 60–6583, Figure 3, the only one selective A2BAR agonist currently available) agonists were also obtained. Antagonists of the ARs have been obtained based on heterocyclic scaffolds. Several of these derivatives are xanthine-based compounds, like DPCPX or 8-CPT (A1AR antagonists, Figure 3), DMPX (A2AAR antagonist, Figure 3) and analogues, istradefylline (A2AAR antagonist clinically approved for Parkinson’s Disease, Figure 3), and PSB 603, MRS 1754, or 8-SPT (A2BAR antagonists, Figure 3), compounds frequently used as pharmacological probes. Non-xanthine-based AR antagonists were developed by using various mono-, bi-, and tri-cyclic scaffolds, obtaining potent, and subtype selective compounds (i.e. ZM241385, MRS 1220, and MRS 1334, Figure 3) [66–70].