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  • Another interesting approach is to use partial

    2021-10-11

    Another interesting approach is to use partial agonists as starting point to develop specific antagonists like done in earlier decades [64], [65]. Possible indications for an attenuation of the NO/sGC signalling pathway might be specific neuronal disorders: an involvement in the aetiology of migraine [66] and Parkinson’s disease [67], [68] has been suggested. Furthermore, a large body of literature discusses the participation of NO/sGC signalling in septic shock [69], [70], [71], [72]. Current sGC inhibitors like nucleotides, heme group oxidants (e.g., ODQ) or allosteric regulators are not suitable for clinical use, as they suffer from weak potency and poor specificity [68], [73], [74], [75], [76]. In contrast, compounds from the sGC activator type are highly specific for sGC. Via the co-translational insertion, they also provide a high potency. A compound derived from a partial agonist but without intrinsic activity might represent a very potent sGC inhibitor. As summarised in Fig. 10, our findings indicate that BR 11257 is a non-stabilising partial agonist of sGC that may increase the cGMP levels depending on the extent of the receptor reserve which may differ from tissue to tissue and in pathophysiological conditions. In addition, a faster off-kinetic may also lead to a shortened blood pressure response in comparison to dicarboxylic agents.
    Introduction There are at least two types of cardiac-derived peptide hormones, namely atrial and brain natriuretic factor or peptides (ANF/ANP, BNP), which mediate natriuretic, diuretic, vasorelaxant, and antimitogenic responses directed to reduce blood pressure and maintain fluid volume homeostasis [[1], [2], [3], [4], [5], [6], [7]]. Both ANP and BNP are primarily synthesized in the heart atrial myocytes and to a lesser extent in the ventricular cells [[8], [9], [10]]. Pro-ANP, but not ANP, is stored in the atrial dense granules [[11], [12], [13]]. ANP is largely released as a 28-amino BET bromodomain inhibitor synthesis residues biologically active mature hormone, whereas BNP is released as a prohormone (Pro-BNP). Upon secretion, Pro-BNP is enzymatically cleaved to produce biologically active 32-residues BNP [[11], [12], [13]]. It is unclear whether BNP or Pro-BNP is stored in those granules, which contain ANP. A third peptide in the natriuretic peptide hormone family, differs from ANP and BNP in the tissue expression and biological function, is known as C-Type natriuretic peptide (CNP), which is highly conserved among species, is basically present in endothelial cells and the central nervous system [14,15]. The receptors of these peptide hormones have been classified as natriuretic peptide receptor-A (NPRA), -B (NPRB), -C (NPRC), and ANF-RGC [[16], [17], [18], [19], [20], [21], [22], [23], [24]]. NPRA and NPRB show similar homology and contain an extracellular ligand-binding domain, a single transmembrane region, and an intracellular region containing both a protein kinase-like homology domain (protein-KHD) and guanylyl cyclase (GC) catalytic domain [16,17,20,[23], [24], [25]]. As shown in Figure 1, both ANP and BNP specifically bind and activate NPRA that produces intracellular second-messenger cGMP in response to hormone binding in various cells and tissues [2,[26], [27], [28], [29]]. BNP is also considered as a neuropeptide hormone, which is expressed in a subset of transient receptor potential vanilloid-1 (TRPV1) neurons. A study showed that Nppb mice selectively lost almost all behavioral responses to itch-inducing agents [30]. CNP activates NPRB that also produces intracellular cGMP [17,24,28,29]. Moreover, all three natriuretic peptides arbitrarily bind to NPRC, which lacks a GC domain and does not produce cGMP [5,22,28,31]. GC-A/NPRA is considered to be the biologically active cognate receptor of both ANP and BNP. Because most of the physiological effects of GC-A/NPRA are triggered by generating second-messenger cGMP, this receptor is generally considered the biologically active cognate receptors of ANP and BNP [5,19,29,[32], [33], [34], [35]].