Bradykinin Receptors

The nonapeptide bradykinin (BK) and Lys-BK (kallidin) are naturally occurring substances produced in most species by the proteolytic digestion of high or low molecular weight kininogen by plasma and tissue kallikrein, respectively, following a suitable stimulus. T-kinin (Ile-Ser-BK) is formed from T-kininogen in the rat. Removal of the C-terminal arginine of BK and Lys-BK by carboxypeptidases generates the peptides BK(1-8), also referred to as [des-Arg9]-BK, and Lys-BK(1-8), also known as [Lys-des-Arg9]-BK or [des-Arg10]-kallidin, respectively. Bradykinin and the related kinins possess a wide range of pharmacological actions and are believed to be important mediators of pain and inflammation in addition to being involved in the control of local blood flow.

Kinins induce their effects via two main types of receptor, designated B1 and B2, both of which belong to the superfamily of G protein-coupled receptors. An orphan GPCR (GPR100) has been suggested to be a candidate BK receptor; however, further detailed characterization is required. BK(1-8) is a more potent agonist at the rodent/murine B1 receptor as compared with its activity at the human B1 receptor for which the B1 agonist of choice is Lys-BK(1-8). The B2 receptor is generally present in a wide variety of tissues. In contrast, the B1 receptor, which is expressed at low levels under normal conditions, appears to be up-regulated both in vitro and in vivo following exposure to noxious stimuli such as LPS and other inflammatory mediators such as IL-1β, IL-2, IL-8, growth factors such as EGF and neurotrophic factors such as NGF.

The molecular cloning of cDNAs encoding the kinin receptors has provided direct evidence for the existence of B1 and B2 receptors as the products of distinct genes. The human, dog, mouse and rat B2 and B1 receptors have been cloned, expressed, sequenced and characterized pharmacologically. Human and rabbit B1 receptors, respectively, exhibit approximately 2,000- and 150-fold higher affinities for Lys-BK(1-8) relative to BK(1-8) whereas the mouse B1 receptor exhibits a 2-3 fold higher affinity for BK(1-8) compared to Lys-BK(1-8). The homology between the human B2 and B1 receptor sequence is only 36% at the amino acid level. In comparison, the human B1 receptor is 30% identical to the AT1 angiotensin II receptor. Many cells co-express both B1 and B2 receptors. Both receptors interact with Gαq and Gαi through which they mediate intracellular signaling, including phosphoinositide hydrolysis and elevation of intracellular calcium.

Activation of both the B1 and the B2 receptor has been implicated in many pathophysiological disorders and efforts have been made to develop selective agonist and antagonist ligands for both receptors for use as pharmacological/biochemical tools and potential therapeutic agents. Blocking both receptors may be beneficial in certain circumstances, such as hyperalgesia, and peptide-based compounds have been developed that display high affinity for both receptors (e.g. B9430). Mice lacking the B1 or B2 receptor are available and are helping to elucidate the role of these receptors in development, and in normal and altered physiology. A wide selection of peptide (first generation), stabilized, more enzyme resistant (second generation) and non-peptide (third generation) agonists and antagonists are now available allowing a more detailed characterization of bradykinin B1 and B2 receptor function both in in vitro and in vivo systems. Antagonists and agonists at either the B1 or B2 receptor have potential therapeutic utility in various disease indications.

 

The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.

 

Currently Accepted Name B1 B2
Alternate Name BK1 BK2
Structural Information 353 aa (human) 364 aa (human)
Type Selective Agonists (Peptide) BK(1-8) (B4397)
Lys-BK(1-8)
Sar[D-Phe8]-BK(1-8)
BK (B3259)
Lys-BK
Ile-Ser-BK (SCP0058)
[Phe8-(ψ-CH2NH)-Arg9]-BK
[Hyp3,Tyr(Me)8]-BK
[Hyp3]-BK (B7775)
RMP-7 (Cereport)
LF 150943
Type Selective Agonist (Non-Peptide) Not Known FR 190997
Type Selective Antagonists (Peptide) [Leu8]-BK(1-8)
Lys-[Leu8]-BK(1-8)
[des-Arg10]-HOE 140
B9958
HOE 140 (H157)
NPC 17731
D-Arg[Hyp3,Thi5,HypE(trans-propyl)7,Oic8]-BK
Type Non-selective Antagonists (Peptide) B-9430 (B3811)
B-9430 (B3811)
Type Selective Antagonists (Non-Peptide) SSR240612 Bradyzide (B1680)
FR 173657
LF 160687
Signal Transduction Mechanisms Gq/11 (increase IP3/DAG) Gq/11 (increase IP3/DAG)
Radioligands of Choice [3H]-Lys-BK(1-8)
[3H]-[des-Arg10,Leu9]-Kallidin
[3H]-[des-Arg10]-Kallidin
[125I]-[Tyr8]-BK
[3H]-BK
[3H]-NPC 17731
Tissue Expression Inducible following tissue injury in most cells and tissues Constitutive: Most cells and tissues
Physiological Function Not Known
Local blood flow
Disease Relevance Pain, inflammation, edema, infection/sepsis, asthma, renal/cardio protection, tumor/angiogenesis
diabetes
Pain, inflammation, edema, CNS trauma/edema/stroke, infection/sepsis, asthma/rhinitis, renal/cardioprotection, tumor/angiogenesis, pancreatitis, hereditary angioneurotic, edema, cirrhosis

 

Abbreviations

BK: Bradykinin
Lys-BK: Kallidin
Ile-Ser-BK: T-Kinin
Bradyzide: (2S)-1-[4-(4-Benzhydrylthiosemicarbazido)-3-nitrobenzenesulfonyl]-pyrrolidine-2-carboxylic acid (2-(2-dimethylaminoethyl)methylamino]ethyl)amide)
B9958: Lys-Lys-Arg-Pro-Hyp-Gly-CpG-Ser-DTic-Cpg
B9430: D-Arg-Arg-Pro-Hyp-Igl-Ser-D-Igl-Oic-Arg
LF 150943 (JMV1116): D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-(3S)[amino]-5-(carbonylmethyl)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one-Arg
LF 160687: 1-[[2,4-dichloro-3-[[(2,4-dimethylquinolin-8-yl)oxy] methyl]phenyl]sulfonyl]-N-[3-[[4-(aminoiminomethyl)phenyl] carbonylamino]propyl]-2(S)-pyrrolidinecarboxamide
FR 173657: ((E)-3(6-Acetamido-3-pyridyl)-N-[N-[2,4-dichloro-3-[(2-methyl-8-quinolyryl)oxymethyl]phenyl]-N-methylaminocarbonylmethyl]acrylamide)
FR 190997: (8-[2,6-Dichloro-3-[N-[(E)-4-(N-methylcarbamoyl)cinnamidoacetyl]-N-methylamino]benzyloxy]-2-methyl-4-(2-pyridylmethoxy)quinoline
HOE 140: D-Arg[Hyp3,Thi5, D-Tic7,Oic8]BK
NPC 17731: D-Arginyl-L-arginyl-L-prolyl-(4R)-4-hydroxy-L-prolylglycyl-L-phenylalanyl-L-seryl-(4S)-4-propoxy-D-prolyl-(2S,3aS,7aS)-octahydro-1H-indole-2-carbonyl-L-arginine
RMP-7 (Cereport): Arg-Pro-Hyp-Gly-Thi-Ser-Pro-4-Me-TyrY((CH2NH)Arg
SSR240162: (2R)-2-[((3R)-3-(1,3-benzodioxol-5-yl)-3-{[(6-methoxy-2-naphtyl)sulphonyl]amino}propanoyl)amino]-3-(4-{[2R,6S)-2,6-dimethylpiperidinyl]methyl}phenyl)-N-isopropyl-N-methylpropanamide hydrochloride

 

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References