New therapeutic target in primary headaches - blocking theCGRP receptor.
The primary headaches are among the most prevalent neurological disorders, afflicting up to 16% of the adult population. The associated pain originates from intracranial blood vessels that are innervated by sensory nerves storing several neurotransmitters. In primary headaches, there is a clear association between the headache and the release of calcitonin gene-related peptide (CGRP), but not other neuronal messengers. The specific purpose of this review is to describe CGRP in the human cranial circulation and to elucidate a possible role for a specific antagonist in the treatment of primary headaches. Acute treatment with administration of a 5-HT(1B/1D) agonist (triptan) results in alleviation of the headache and normalisation of the CGRP level. The mechanism of action of triptans involves vasoconstriction of intracranial vessels and a presynaptic inhibitory effect of sensory nerves. The central role of CGRP in migraine and cluster headache pathophysiology has led to the search for small-molecule CGRP antagonists, which are predicted to have fewer cardiovascular side effects in comparison to the triptans. The initial pharmacological profile of such a group of compounds has recently been disclosed. These compounds have high selectivity for human CGRP receptors and are reportedly efficacious in the relief of acute attacks of migraine.
Edvinsson
Lars
L
Department of Internal Medicine, University Hospital, S-221 85 Lund, Sweden. lars.edvinsson@med.lu.se
D000293:Adolescent; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D002116:Calcitonin / Q000037:antagonists & inhibitors / Q000502:physiology; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002648:Child; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D006261:Headache / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008881:Migraine Disorders / Q000188:drug therapy / Q000503:physiopathology; D018377:Neurotransmitter Agents; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D011498:Protein Precursors / Q000037:antagonists & inhibitors / Q000502:physiology; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014276:Trigeminal Nerve / Q000503:physiopathology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D018712:Analgesics, Non-Narcotic; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D018377:Neurotransmitter Agents; D010879:Piperazines; D011498:Protein Precursors; D011799:Quinazolines; D018015:Receptors, Calcitonin Gene-Related Peptide; D002116:Calcitonin; C406305:olcegepant