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CGRP and PACAP are elevated during a migraine attack, and following infusion of either peptide, patients develop migraine\u2010like attacks. This indicates that targeting both these systems may provide therapeutic benefits. Mechanistic studies suggest that these peptides largely act independently from one another. Therefore, blocking the activity of both CGRP and PACAP simultaneously could provide a clinical advantage over individual blockade. One strategy is to develop a single antagonist capable of inhibiting the signaling of both CGRP and PACAP receptors, a multi\u2010receptor antagonist. N\u2010terminal truncation of CGRP and PACAP generates the antagonists CGRP\n                      <jats:sub>8\u201037<\/jats:sub>\n                      and PACAP\n                      <jats:sub>6\u201038<\/jats:sub>\n                      , respectively. These are commonly used as research tools for the CGRP and PACAP receptors. These peptide antagonists were, therefore, used as the basis for the design of multi\u2010receptor antagonists against the CGRP and PACAP receptors and to test their functionality in\u00a0vitro.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To generate multi\u2010receptor antagonists, CGRP\n                      <jats:sub>8\u201037<\/jats:sub>\n                      was linked through 1,3\u2010dipolar cycloaddition using click chemistry to PACAP\n                      <jats:sub>6\u201038<\/jats:sub>\n                      at amino acid residues 21, 34, or 38. The ability of these multi\u2010receptor antagonists to block CGRP activity (CGRP and AMY\n                      <jats:sub>1<\/jats:sub>\n                      receptors) and PACAP\u201038, PACAP\u201027, and VIP activity (PAC\n                      <jats:sub>1<\/jats:sub>\n                      , VPAC\n                      <jats:sub>1<\/jats:sub>\n                      , and VPAC\n                      <jats:sub>2<\/jats:sub>\n                      receptors) was then characterized in transfected Cos7 cells. The peptides were then further examined in pain\u2010relevant rat spinal cord cultures, as a model of endogenous receptors.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Multi\u2010receptor antagonists were successfully generated, displaying similar antagonist potency to their parental antagonists in both transfected Cos7 cells and in spinal cord cultures. Interestingly, CGRP\n                      <jats:sub>8\u201037<\/jats:sub>\n                      linked to position 38 of PACAP\n                      <jats:sub>6\u201038<\/jats:sub>\n                      was a more potent antagonist of CGRP activity than CGRP\n                      <jats:sub>8\u201037<\/jats:sub>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study provides proof\u2010of\u2010concept evidence for the development of potent multi\u2010receptor antagonists capable of blocking both CGRP and PACAP activity.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/head.14916","type":"journal-article","created":{"date-parts":[[2025,3,4]],"date-time":"2025-03-04T03:32:53Z","timestamp":1741059173000},"page":"1064-1079","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Development and pharmacological characterization of novel multi\u2010 calcitonin gene\u2010related peptide and pituitary adenylate cyclase\u2010activating peptide receptor antagonists"],"prefix":"10.1111","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7652-6004","authenticated-orcid":false,"given":"Zoe","family":"Tasma","sequence":"first","affiliation":[{"name":"School of Biological Sciences The University of Auckland  Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Siow","sequence":"additional","affiliation":[{"name":"School of Chemical Sciences The University of Auckland  Auckland New\u00a0Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul W. 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