Small molecule antagonists of the bradykinin B1 receptor

Horlick, Robert A.; Ohlmeyer, Michael; Stroke, Ilana L.; Strohl, Barbara; Pan, Gonghua; Schilling, Adriane; Paradkar, Vidyadhar M.; Quintero, Jorge G.; You, Ming; Riviello, Christopher; Thorn, Megan B; Damaj, Bassam B.; Fitzpatrick, Veronica; Dolle, Roland E.; Webb, Maria L.; Baldwin, John J.; Sigal, Nolan H.

doi:10.1016/s0162-3109(99)00130-7

Cited by 28 publications

(17 citation statements)

References 19 publications

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“…Recently, the results of research into the development of B 1 receptor antagonists as novel therapeutic agents have begun to bear fruit. In 1999, researchers from Pharmacopeia published on a compound PS020990 as a potent and competitive B 1 receptor antagonist (Horlick et al, 1999). PS020990 was derived from compounds discovered from the screening of a combinatorial chemistry library and is the first nonpeptide B 1 receptor antagonist described in the literature.…”

Section: Nonpeptide Ligandsmentioning

confidence: 99%

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

Marceau²,

et al. 2005

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Section: Nonpeptide Ligandsmentioning

confidence: 99%

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

Marceau²,

et al. 2005

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“…Bradykinin B 1 receptors [26,27] Glutamate, Kainate receptors [54]. Source: Wistar rat brain (minus cerebellum).…”

Section: Radioligand Binding Assaysmentioning

confidence: 99%

From Anti-allergic to Anti-Alzheimer ’ s: Molecular Pharmacology of Dimebon™

Okun¹,

Ткаченко²,

Khvat³

et al. 2010

CAR

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Dimebon, originally developed as an anti-histamine drug, is being re-purposed for new indications as an effective treatment for patients suffering from Alzheimer's and Huntington's diseases, albeit with an as-yet unknown mechanism of action. We have performed molecular pharmacology profiling of this drug on a panel of 70 targets to characterize the spectrum of its activity, with the goal to possibly elucidate a potential molecular mechanism for the re-purposing of this drug candidate. We show that in addition to histaminergic receptors, Dimebon exhibits high affinity to a constellation of other receptors; specifically serotonergic, alpha-adrenergic and dopaminergic receptors. Good correlations with published literature were obtained for the affinity of Dimebon to inhibit butyrylcholinesterase, interact with H1and H2 receptors (Ki = 2 nM and 232 nM), and to block histamine-induced calcium fluxes in cells. Within serotonergic receptor subtypes, Dimebon shows highest affinity for 5-HT7 (Ki=8 nM) and 5-HT6 (Ki=34 nM) receptors, with the relative affinity rank-order of 5-HT7 > 5-HT6 > or = 5-HT2A = 5-HT2C > 5-HT1A = 5-HT1B > 5-HT2B=5-HT3. Dimebon also interacts with adrenergic receptor subtypes (rank-order: alpha1A (Ki = 55 nM)= alpha1B > or = alpha2A (Ki = 120 nM) = alpha1D), and dopaminergic receptor subtypes (rank-order: D1=D2S=D2L (Ki approximately 600 nM) >D3> or =D4.2>D4.4> or =D4.7). These results demonstrate a molecular pharmacological basis for re-purposing of this drug to new therapeutic areas. The informed targeting of the combined molecular target activities may provide additional advantages for patients suffering from similar diseases syndromes. Understanding the role that different pathways play in diseases with complex etiologies may allow for the rational design of multi-target drugs.

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“…Numerous research groups have developed peptide and non-peptide selective BKB 1 -R antagonists to identify the pathophysiological role of the inducible BKB1-R subtype (Hanson et al, 1996;Horlick et al, 1999;Stewart et al, 1999;Gabra et al, 2002;Neugebauer et al, 2002;Su et al, 2003;Gougat et al, 2004;Marceau and Regoli, 2004;Pruneau et al, 2004;Ritchie et al, 2004;Fox et al, Brought to you by | Tokyo Daigaku Authenticated Download Date | 5/30/15 5:26 PM Figure 4 Immunohistological localization of the inducible BKB 1 -R subtype in the skin of STZ-diabetic rats (A) and spinal cord from NOD mice (B). Co-localization with von-Willebrand factor, a marker for blood vessels.…”

Section: Development Of Selective Bkb1-r Antagonistsmentioning

confidence: 99%

The kinin system mediates hyperalgesia through the inducible bradykinin B1 receptor subtype: evidence in various experimental animal models of type 1 and type 2 diabetic neuropathy

Gabra

Berthiaume²,

Sirois

et al. 2006

Biological Chemistry

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Both insulin-dependent (type 1) and insulin-independent (type 2) diabetes are complex disorders characterized by symptomatic glucose intolerance due to either defective insulin secretion, insulin action or both. Unchecked hyperglycemia leads to a series of complications among which is painful diabetic neuropathy, for which the kinin system has been implicated. Here, we review and compare the profile of several experimental models of type 1 and 2 diabetes (chemically induced versus gene-prone) and the incidence of diabetic neuropathy upon aging. We discuss the efficacy of selective antagonists of the inducible bradykinin B1 receptor (BKB1-R) subtype against hyperalgesia assessed by various nociceptive tests. In either gene-prone models of type 1 and 2 diabetes, the incidence of hyperalgesia mostly precedes the development of hyperglycemia. The administration of insulin, achieving euglycemia, does not reverse hyperalgesia. Treatment with a selective BKB1-R antagonist does not affect basal nociception in most normal control rats, whereas it induces a significant time- and dose-dependent attenuation of hyperalgesia, or even restores nociceptive responses, in experimental diabetic neuropathy models. Diabetic hyperalgesia is absent in streptozotocin-induced type 1 diabetic BKB1-R knockout mice. Thus, selective antagonism of the inducible BKB1-R subtype may constitute a novel and potential therapeutic approach for the treatment of painful diabetic neuropathy.

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Small molecule antagonists of the bradykinin B1 receptor

Cited by 28 publications

References 19 publications

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

From Anti-allergic to Anti-Alzheimer ’ s: Molecular Pharmacology of Dimebon™

The kinin system mediates hyperalgesia through the inducible bradykinin B1 receptor subtype: evidence in various experimental animal models of type 1 and type 2 diabetic neuropathy

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Small molecule antagonists of the bradykinin B1 receptor

Cited by 28 publications

References 19 publications

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

From Anti-allergic to Anti-Alzheimer ’ s: Molecular Pharmacology of Dimebon&#8482;

The kinin system mediates hyperalgesia through the inducible bradykinin B1 receptor subtype: evidence in various experimental animal models of type 1 and type 2 diabetic neuropathy

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From Anti-allergic to Anti-Alzheimer ’ s: Molecular Pharmacology of Dimebon™