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Non-adrenergic Non-cholinergic Autonomic Transmission
Published in Kenneth J. Broadley, Autonomic Pharmacology, 2017
After its release, ATP is broken down by the ectoenzyme, 5′-nucleotidase, which is located on the smooth muscle cell membrane. The product of this degradation is adenosine, which is then rapidly taken up by the neurone or by the effector cells through facilitated diffusion or the ‘adenosine transporter’ system. This is carrier-mediated and capable of competitive inhibition by drugs such as dipyridamole and dilazep, which generally affect both the influx (uptake) and eflux of adenosine. Thus, adenosine is conserved and resynthesized to ATP within the neurone, firstly to 5’-nucleotide via adenosine kinase (Broadley 1995). The adenosine produced by breakdown of the released ATP may therefore exert some of the pharmacological effects of NANC nerve stimulation.
Drug Combinations
Published in Josef Hladovec, Antithrombotic Drugs in Thrombosis Models, 2020
The effectiveness of dipyridamole in combination with adenosine or its derivatives has been suggested on the basis of the supposed mechanism of dipyridamole action, i.e., inhibition of adenosine accumulation in cells. Thus, the inhibitory adenosine effects on white body formation in the rabbit and rat cerebral cortex microcirculation were particularly potentiated by dipyridamole59 and potentiation was likewise observed in vitro by Dawicki et al.,60 who also used some drugs related to dipyridamole (dilazep and RA 233). Other studies have shown a potentiation by dipyridamole of prostacyclin effects on platelet adhesion to collagen-coated glass.61 The inhibitory effects of the combination of eterylate (derivative of ASA) with dipyridamole were demonstrated in collagen and epinephrine-induced DIC in mice by Ortega.62 Harker63 stated, on the basis of his experience with the cannula platelet consumption rate in baboons, that the combination of dipyridamole and sulfinpyrazone has only additive inhibitory effects. In vitro potentiation of aggregation inhibition by dipyridamole was systematically investigated by Praga et al.64 Particularly effective were ergoline derivatives, metergoline, and nimergoline. Clinical ex vivo platelet studies have shown positive effects of the combination nifedipine-dipyridamole in ischemic heart disease.65 Vermylen et al.66 observed ex vivo potentiation of the dipyridamole antiaggregatory effect by nafazatrom probably due to a complementary effect on the prostacylin level.
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
Modulators of the nucleoside transporters (both ENTs and CNTs) activity were developed based on purine or pyrimidine nucleoside structure. Among these compounds is the ENT1 inhibitor nitrobenzylthioinosine (NBMPR, Figure 4) [76]. Another purine nucleoside derivative is 5-iodotubercidin (Figure 4), a potent ADK inhibitor able also to inhibit nucleosides transporters. Modification of uridine led to the recent development of the compound MeThPmR (Figure 4), inhibitor of CNTs as well as its 2ʹ-deoxy analogue [77]. Non-nucleoside inhibitors (Figure 4) of nucleoside transporters are dilazep, dipyridamole, and lidoflazine, compounds based on various scaffolds.