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  • 4a 5 2 3.25 a br No Evidence for Further ET Receptor Subtype


    No Evidence for Further ET-Receptor Subtypes Further receptor subclassifications have been proposed including suggestions that ETB could be subdivided into ETB1, present on endothelial cells, and ETB2 on smooth muscle cells, but there currently is no evidence that the receptors expressed by these two cell types can be distinguished pharmacologically.10, 11 ET-receptor antagonists have not been successful in certain conditions such as heart failure, perhaps implying that ETs may mediate their actions via previously unsuspected receptors; however, this is unlikely. Following the sequencing of the human genome, it is accepted that all 4a 5 2 3.25 a that potentially encode a G-protein–coupled receptor have been identified and currently are classified as ‘orphan’ to indicate that their endogenous ligand is not yet known.13, 14 These remaining orphan receptors (approximately 80) have been screened against more than 20 ET peptides (including all three endogenous isoforms and their corresponding big ET precursors, C-terminal metabolites, the ETA antagonist BQ123, and the ETB agonist BQ3020) without detectable binding. The screen also included two of the most closely related orphan receptors to ETA and ETB, GPR37 (also known as endothelin-receptor type B-like receptor or Parkin-associated endothelin receptor-like receptor) and its related receptor GPR37L1. Two neuropeptides, prosaptide and prosaposin, that are structurally distinct from the ETs have been suggested to be the endogenous ligands for GPR37 and GPR37L1.
    Peptide Agonists Experimental medicine studies in volunteers mainly use ET-1 that is equipotent for ETA and ETB (Table 1). ET-3, which is modestly selective for ETB, also has been used but greater ETB selectivity is shown by sarafotoxin S6c, one of the isoforms originally identified from snake venom. IRL1620 (Suc-[Glu,Ala11, 15]-endothelin-18-21) is a truncated linear analogue in which the N-terminus has an N-succinyl modification, reducing metabolism by nonspecific peptidases. It was developed as an ETB agonist but now is used in clinical trials as a potential vasodilator in the delivery of anticancer agents and in neuroprotection where it is known as SPI-1620 (licensed by Spectrum Pharmaceuticals, Henderson, NV). The second widely used ETB agonist is BQ3020 ([Ala11, 15]Ac-ET-l6-21), however, this compound has not been used clinically.
    Peptide Antagonists The first endothelin-receptor antagonists to be discovered were from natural product screening, compound libraries, or drug design based on the structure of the endogenous ET peptides (Table 1). The most widely used, according to the number of published articles, is the cyclic pentapeptide BQ-123 (D-Asp-L-Pro-D-Val-L-Leu-D-Trp-) (Ihara et al), based on peptides isolated from Streptomyces misakiensis, a highly selective competitive ETA antagonist with low nanomolar affinity for the receptor. The second most widely used is FR 139317 (N-[(hexahydro-1-azepinyl)carbonyl]L-Leu[1-Me]D-Trp-3 [2-pyridyl]-D-Ala), a linear tripeptide. These are 4a 5 2 3.25 a both highly ETA selective for human (as well as rodent) ET receptors and at concentrations used in experimental medicine or in vivo animal experiments are likely to block only the ETA receptor; data from these studies can be interpreted with confidence. TAK-044 is a cyclic hexapeptide also isolated from S misakiensis with a more modest degree of ETA selectivity. BQ788 (N-[([2R,6S]-2,6-dimethyl-1-piperidinyl)carbonyl]-4-methyl-L-leucyl-N-[(1R)-1-carboxylatopentyl]-1-[methoxycarbonyl]-D-tryptophanamide) is a modified tripeptide developed by structure-activity analysis and is a selective competitive ETB antagonist (usually showing one to two orders of magnitude selectivity for ETB over ETA) in human beings and across species. Because these compounds are all peptides, they have little or no oral bioavailability, require intra-arterial administration, and are metabolized or excreted over comparatively short periods of time. An advantage in their use is that they are soluble and do not bind plasma proteins. Therefore, they are used for short-term, acute investigations in both animal models and in experimental medicine studies.