Binding and functional pharmacological characteristics of gepant-type antagonists in rat brain and mesenteric arteries

Sheykhzade, Majid; Amandi, Nilofar; Vidal, M.; Abdolalizadeh, Bahareh; Sams, Anette; Warfvinge, Karin; Edvinsson, Lars; Pickering, Darryl S.

doi:10.1016/j.vph.2017.02.001

Cited by 19 publications

(17 citation statements)

References 32 publications

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“…They have similar affinities on mesenteric arteries and in binding assays to rat brain apart from rimagepant, which shows a 50‐fold lower affinity to brain. The reasons for this discrepancy are unclear (Sheykhzade et al, ). The selectivity of olcegepant and telcagepant for human CGRP and AMY 1(a) receptors has been compared at receptors transfected into Cos‐7 cells.…”

Section: Developments With Antagonistsmentioning

confidence: 99%

Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25

Hay

Garelja

Poyner

et al. 2017

British J Pharmacology

311

441

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The calcitonin/CGRP family of peptides includes calcitonin, α and β CGRP, amylin, adrenomedullin (AM) and adrenomedullin 2/intermedin (AM2/IMD). Their receptors consist of one of two GPCRs, the calcitonin receptor (CTR) or the calcitonin receptor-like receptor (CLR). Further diversity arises from heterodimerization of these GPCRs with one of three receptor activity-modifying proteins (RAMPs). This gives the CGRP receptor (CLR/RAMP1), the AM and AM receptors (CLR/RAMP2 or RAMP3) and the AMY AMY and AMY receptors (CTR/RAMPs1-3 complexes, respectively). Apart from the CGRP receptor, there are only peptide antagonists widely available for these receptors, and these have limited selectivity, thus defining the function of each receptor in vivo remains challenging. Further challenges arise from the probable co-expression of CTR with the CTR/RAMP complexes and species-dependent splice variants of the CTR (CT and CT ). Furthermore, the AMY receptor is activated equally well by both amylin and CGRP, and the preferred receptor for AM2/IMD has been unclear. However, there are clear therapeutic rationales for developing agents against the various receptors for these peptides. For example, many agents targeting the CGRP system are in clinical trials, and pramlintide, an amylin analogue, is an approved therapy for insulin-requiring diabetes. This review provides an update on the pharmacology of the calcitonin family of peptides by members of the corresponding subcommittee of the International Union of Basic and Clinical Pharmacology and colleagues.

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Section: Developments With Antagonistsmentioning

confidence: 99%

Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25

Hay

Garelja

Poyner

et al. 2017

British J Pharmacology

311

441

View full text Add to dashboard Cite

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“…55 This high-affinity binding event greatly increases local concentration of CGRP, allowing the lower affinity interaction of the N-terminal of the CGRP peptide agonist with the juxtamembrane region of CLR activating the RCP signaling cascades. 70 Additional residues (Arg67, Asp71, Glu78, and Trp84) may interact with small molecule CGRP-RAs with limited evidence on potency. For CLR-RAMP1 antagonism, the extracellular N-terminus amino acid residues Tryptophan 74 of RAMP1 and Methionine 42 in CLR are clustered on the molecular surface and identified as critical for cell surface expression of the CLR-RAMP1 heterodimer.…”

Section: Cgrp Receptor Antagonist Specificsmentioning

confidence: 99%

“…For CLR-RAMP1 antagonism, the extracellular N-terminus amino acid residues Tryptophan 74 of RAMP1 and Methionine 42 in CLR are clustered on the molecular surface and identified as critical for cell surface expression of the CLR-RAMP1 heterodimer. 70 Moore et al state that, "one must keep in mind that the selectivity profile of each class of molecule may be quite divergent, and there is in all likelihood a diverse palette of approaches that could be developed to block CGRP from interacting with its receptor." 67 The CLR αC1 helix and the RAMP1 αR2 helix form a hydrophobic-binding pocket, preventing the initial C-terminal CGRP-binding event and receptor activation.…”

Section: Cgrp Receptor Antagonist Specificsmentioning

confidence: 99%

“…They essentially act as an irreversible antagonist under those conditions. 70 Additional residues (Arg67, Asp71, Glu78, and Trp84) may interact with small molecule CGRP-RAs with limited evidence on potency. 48,52 The RAMP1 N-terminus Tryptophan 84 Alanine residue has been identified as important in both agonist and antagonist binding in both CGRP and AMY 1 receptors.…”

Section: (A) the C-terminal Of Cgrp First Binds With High Affinity Tomentioning

confidence: 99%

“…For example, rimegepant appears to have very similar binding affinities and effects to telcagepant. 70 Moore et al state that, "one must keep in mind that the selectivity profile of each class of molecule may be quite divergent, and there is in all likelihood a diverse palette of approaches that could be developed to block CGRP from interacting with its receptor." 48…”

Section: (A) the C-terminal Of Cgrp First Binds With High Affinity Tomentioning

confidence: 99%

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CGRP, Amylin, Immunology, and Headache Medicine

Taylor

2018

Headache

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Background Calcitonin gene‐related peptide (CGRP) therapeutics introduce new excitement and possibly yet to be determined distressing discords in the field of Headache Medicine. Growth in knowledge of CGRP in the pathophysiology of migraine introduced CGRP antagonism to headache treatment. Potential adverse effects on the other circulatory and neurovascular diseases have been foremost concerns. Failures in development of gepants and growth in knowledge of monoclonal antibody therapeutics combined to deliver the anti‐CGRP monoclonal antibodies (mAbs). Current Situation as of July 2018 Erenumab, eptinezumab, fremanezumab, and galcanezumab are approved, submitted to, or preparing for submission at both the European Medicines Agency and the US Food and Drug Administration (FDA). Methods This Headache Currents update emanates from a symposium on CGRP and immunology in Headache Medicine, and reviews both. Results and Conclusion Understanding CGRP in Headache Medicine requires information on aspects of the CGRP ligand, cell surface G protein receptor, CGRP receptor specifics, and antagonism by CGRP small and large molecules. Recent reports of CGRP’s high affinity for amylin receptors dictate some attention to this family‐related peptide. To better understand potential immunogenic risks and off‐target toxicities of the anti‐CGRP monoclonal antibodies, this review discusses immunology and CGRP and reviews IgG structure and function, monoclonal antibody production, ligand–antigen–antibody relationships, and clinical CGRP mAb specifics. Upon completion, the reader should better summarize CGRP antagonist fundamentals, recall antibody structure and function, restate therapeutic mAbs attributes, and appraise immunogenic risks.

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Anti‐migraine Calcitonin Gene–Related Peptide Receptor Antagonists Worsen Cerebral Ischemic Outcome in Mice

Mulder

Vries

et al. 2020

Annals of Neurology

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Objective: Calcitonin gene-related peptide (CGRP) pathway inhibitors are emerging treatments for migraine. CGRPmediated vasodilation is, however, a critical rescue mechanism in ischemia. We, therefore, investigated whether gepants, small molecule CGRP receptor antagonists, worsen cerebral ischemia. Methods: Middle cerebral artery was occluded for 12 to 60 minutes in mice. We compared infarct risk and volumes, collateral flow, and neurological deficits after pretreatment with olcegepant (single or 10 daily doses of 0.1-1mg/kg) or rimegepant (single doses of 10-100mg/kg) versus vehicle. We also determined their potency on CGRP-induced relaxations in mouse and human vessels, in vitro. Results: Olcegepant (1mg/kg, single dose) increased infarct risk after 12-to 20-minute occlusions mimicking transient ischemic attacks (14/19 vs 6/18 with vehicle, relative risk = 2.21, p < 0.022), and doubled infarct volumes (p < 0.001) and worsened neurological deficits (median score = 9 vs 5 with vehicle, p = 0.008) after 60-minute occlusion. Ten daily doses of 0.1 to 1mg/kg olcegepant yielded similar results. Rimegepant 10mg/kg increased infarct volumes by 60% after 20-minute ischemia (p = 0.03); 100mg/kg caused 75% mortality after 60-minute occlusion. In familial hemiplegic migraine type 1 mice, olcegepant 1mg/kg increased infarct size after 30-minute occlusion (1.6-fold, p = 0.017). Both gepants consistently diminished collateral flow and reduced reperfusion success. Olcegepant was 10-fold more potent than rimegepant on CGRP-induced relaxations in mouse aorta. Interpretation: Gepants worsened ischemic stroke in mice via collateral dysfunction. CGRP pathway blockers might thus aggravate coincidental cerebral ischemic events. The cerebrovascular safety of these agents must therefore be better delineated, especially in patients at increased risk of ischemic events or on prophylactic CGRP inhibition.

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Binding and functional pharmacological characteristics of gepant-type antagonists in rat brain and mesenteric arteries

Cited by 19 publications

References 32 publications

Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25

Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25

CGRP, Amylin, Immunology, and Headache Medicine

Anti‐migraine Calcitonin Gene–Related Peptide Receptor Antagonists Worsen Cerebral Ischemic Outcome in Mice

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