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Dopamine Receptors, Signaling Pathways, and Drugs
Published in Nira Ben-Jonathan, Dopamine, 2020
Fenoldopam, a benzazepine derivative, is a peripheral D1R agonist. Administered parenterally, fenoldopam acts as a vasodilator in the peripheral arteries, and as a diuretic in the kidneys. Fenoldopam has been approved by the FDA in 1997 for in-hospital, short-term management of severe hypertension, when a rapid, but a reversible, reduction of blood pressure is required [76]. Hypertensive emergencies that use fenoldopam include accelerated hypertension, hypertensive encephalopathy, acute left ventricular failure, acute aortic dissection, pheochromocytoma crisis, interaction between tyramine-containing foods or drugs and monoamine oxidase inhibitors, eclampsia, drug-induced hypertension, and occasionally intracranial hemorrhage.
Imaging Neuroreceptors to Study Drug Action in Living Human Brain
Published in Edythe D. London, Imaging Drug Action in the Brain, 2017
In 1972, Kebabian et al. discovered a dopamine-sensitive adenylate cyclase in rat striatum. The Dl and D2 dopamine receptor subtypes were later defined in 1979 by Kebabian et al. The D1 receptor was defined initially as being coupled to adenylate cyclase, whereas the D2 receptor was defined as either being uncoupled or inhibitory to this system. Investigation of the D1 dopamine receptor was dramatically enhanced with development of the benzazepine SCH 23390 (Iorio et al., 1983), which labels D1 dopamine receptors specifically (Hyttel, 1983). This D1 dopamine antagonist has been subsequently labeled with 11C (Ravert et al., 1987) and has been imaged in baboons and in human beings. Studies involving normal volunteers and schizophrenic patients (Farde et al., 1987) have been carried out with 11C-SCH 23390. The availability of this ligand, along with other radioligands for D2 dopamine receptors, will allow future investigations of the interaction between D1 and D2 receptors in health and disease. The balance between these two receptor systems may be of significance in determining the therapeutic efficacy of certain drugs, such as clozapine, an atypical neuroleptic, which have mixtures of D1 and D2 binding. Indeed, clozapine itself has recently been radiolabeled and imaged both in striatal and frontal human tissue by PET (Lundberg et al., 1989).
Classification Of Peripheral Dopamine Receptors
Published in M.D. Francesco Amenta, Peripheral Dopamine Pathophysiology, 2019
Agonists produced dose-related increases in mesenteric blood flow in the anesthetised cat and dog. In the rabbit isolated splenic artery and human basilar artery, contracted with prostaglandin F2α (PGF2α), they caused relaxation. Results obtained are shown in Table 2. Most compounds produced a similar profile of activity in both the cat and dog mesenteric vascular beds, suggesting that their effects were mediated through a common type of receptor. However, the results obtained with the benzazepines SK&F 38393 and fenoldopam (SK&F 82526) suggest that this view may be oversimplistic. Both of these compounds were potent agonists in the dog mesenteric vascular beds. Fenoldopam, but not SK&F 38393, was also a potent dilator in the cat mesenteric vascular bed. However, both compounds exerted little relaxant activity in the rabbit splenic artery. SK&F 38393 was also a weak agonist in the human basilar artery. Fenoldopam has not been tested in this latter preparation. In essence, SK&F 38393 and fenoldopam acted primarily as weak antagonists in the rabbit splenic artery as they both antagonized the relaxant effect of dopamine (pA2 values = 6.43 and 5.48, respectively). Indeed the antagonist effects of fenoldopam in this tissue suggest that this compound may act as a selective antagonist of the vascular dopamine receptor in, for example, the rabbit splenic artery whereas it acts as an agonist at other vascular dopamine receptors. In contrast to our findings, other workers have reported variable results for fenoldopam and SK&F 38393 in the rabbit splenic artery. Ohlstein et al.17 also have reported that fenoldopam acts as a weak agonist in PGF2a or potassium-contracted tissues, whereas Clark found fenoldopam to be more potent than dopamine in these preparations when contracted with PGF2a.37 Nonetheless, our results taken as a whole suggest that different types of vascular dopamine receptors may occur which may be species or strain dependent. However, an alternative explanation of the results obtained with SK&F 38393 and fenoldopam is that these compounds have low efficacy and behave as weak partial agonists in the rabbit splenic artery. This would be the case if the receptors in this tissue are poorly coupled compared with the receptors in the cat and dog mesenteric vascular bed. In recent experiments, we have attempted to improve the efficiency of the coupling process by inhibiting the breakdown of cAMP with 3-isobutyl-l-methyl xanthine (IBMX).18 Under these circumstances, the potency of dopamine was potentiated, and so too, in some experiments, was that of dopamine and fenoldopam. However, the effects of SK&F 38393, unlike those of dopamine and fenoldopam were not, and we have yet to demonstrate that the effects of fenoldopam are antagonized by SCH 23390. Consequently, the basis of the agonist activity of fenoldopam in the rabbit splenic artery remains controversial.
Vasopressin receptor antagonists: a patent summary (2018-2022)
Published in Expert Opinion on Therapeutic Patents, 2023
Ferenc Baska, Éva Bozó, Tamás Patócs
Researchers at the Xuzhou Medical University discovered new benzodiazepine derivatives as novel V2 receptor antagonists for the treatment of autosomal dominant kidney disease [72]. In 2022 they published benzazepine compounds (31, Figure 8) as a potential treatment or prevention of disorders including hypertension, dysmenorrhea, adrenal hyperplasia, chronic congestive heart failure, liver cirrhosis, depression, hyponatremia, or PKD [73]. An in vivo test was performed to determine the antagonistic effect of compounds on arginine vasopressin receptors by inhibiting the action of cAMP using PKD1 knockout mice. Results revealed that these compounds significantly delayed the occurrence and development of PKD compared with tolvaptan and control. In another patent application, benzodiazepine pyrrole compounds (32, Figure 8) are described by Xuzhou Medical University [74]. The compounds are arginine vasopressin V2 receptor antagonists that can be used as pharmacological tools in studying the kinetics of receptor-ligand binding.
Dopamine-induced functional activation of Gαq mediated by dopamine D1-like receptor in rat cerebral cortical membranes
Published in Journal of Receptors and Signal Transduction, 2019
Yuji Odagaki, Masakazu Kinoshita, Toshio Ota
In summary, [35S]GTPγS binding/immunoprecipitation assay [7] can be applied for functional activation of Gαq coupled to dopamine and 5-HT receptors in rat brain membranes. The response elicited by dopamine and 5-HT is mediated by dopamine D1-like and 5-HT2A receptor, respectively. The dopamine D1-like receptor coupled with Gαq is stimulated by a series of benzazepine derivatives with varied efficacies. It is also activated by SKF83566 and R(+)-SCH23390, both of which are usually known as a selective dopamine D1-like receptor antagonist, as well as by pergolide. The pharmacological characterization indicates the responses induced by these three compounds are mediated by 5-HT2A receptor, but not dopamine D1-like receptor. Caution should be paid when interpreting the experimental data, especially in behavioral pharmacological research, in which SKF83566 or R(+)-SCH23390 is used as a standard selective dopamine D1-like receptor antagonist. Finally, possible clinical implications of the agonistic effects of pergolide on 5-HT2A receptor has been considered.
What place do carbamazepine-related antiepileptic drugs have in the modern day treatment of epilepsy?
Published in Expert Opinion on Pharmacotherapy, 2020
Simona Lattanzi, Vincenzo Belcastro
One major issue is how to best combine di-benzazepine carboxamides for patients requiring polytherapy. Rational polypharmacy is aimed to maximize efficacy and minimize side effects and favorable combinations generally consist of ASMs with different mechanisms of action. Most of the available evidence comes from preclinical studies. In experimental models, coadministration of CBZ and valproic acid (VPA) showed additive antiseizure activity and infra-additive toxicity. Concomitant use of CBZ and phenobarbital (PB) resulted into additivity both in efficacy and toxicity. The coadministration of CBZ or OXC with lamotrigine (LTG) was accompanied by anticonvulsant antagonism and neurotoxic additivity. When OXC was combined with phenytoin (PHT), anticonvulsant infra-additivity was evident at the ratio of 1:1 and additivity at other dose ratios; neurotoxicity additivity occurred at all dose ratios. Gabapentin (GBP) combined with CBZ produced supra-additive efficacy and additive neurotoxicity in the chimney test. Supra-additivity or additivity in seizure control was found in combinations between classical and newer ASMs, including CBZ+topiramate (TPM), CBZ+zonisamide, CBZ+levetiracetam (LEV), CBZ+pregabalin (PGB). Anticonvulsant synergy and additive toxicity occurred combining OXC+TPM. Coadministration of OXC with GBP resulted in supra-additive efficacy and no signs of adverse effects. OXC with tiagabine determined additive efficacy and infra-additive toxicity. Additivity in either efficacy or toxicity was shown when OXC was combined with PGB. OXC+LEV resulted in additive or supra-additive efficacy with no accompanying neurotoxicity. There is only a little evidence about combinations of more than two ASMs: CBZ, PB, and TPM at the fixed-dose ratio of 1:1:1 proved supra-additive effect against seizures [13].