Imaging Neuroreceptors to Study Drug Action in Living Human Brain
Edythe D. London in 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
M.D. Francesco Amenta in Peripheral Dopamine Pathophysiology, 2019
Antagonist potencies are usually considered to be more reliable measures in characterizing receptors. This is because misleading results obtained with agonists, in tissues with poor receptor-response coupling systems, are excluded. In addition, the effects of agonists mediated via other receptors are often difficult to exclude. A wide range of antagonists was evaluated. Most were available because of their clinical use as neuroleptic agents. One exception was SCH 23390. This compound is not used clinically and is a close analogue of the benzazepine agonists SK&F 38393 and fenoldopam. SCH 23390 was the most potent and specific antagonist at vascular dopamine receptors. Domperidone was the least potent. Antagonist potencies at vascular dopamine receptors in the dog and cat (where studied) mesenteric vascular beds were almost identical. Consequently the receptor populations appear identical. However, a different profile of antagonist potencies was obtained in the rabbit splenic artery and human basilar artery compared to the cat and dog mesenteric vascular beds. These are shown in Table 4. The data can most simply be considered by ascribing SCH 23390 the value of unity in the dog mesentery and rabbit splenic artery, respectively. The numerical rank orders of potency produced, also illustrated in Table 4, are strikingly different. These differences are generally maintained if any of the other compounds is given the value of unity. Consequently, the data obtained with antagonists support the suggestion made using agonists that although receptors in the cat and dog mesenteric vascular beds are similar, they differ from those in the rabbit splenic and human basilar arteries. Moreover, the receptors in these latter two preparations appear similar. Thus two distinct, discrete subpopulations of vascular dopamine receptors may well exist.
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].
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