Structure–Activity Studies of Cysteine‐Rich α‐Conotoxins that Inhibit High‐Voltage‐Activated Calcium Channels via GABA_B Receptor Activation Reveal a Minimal Functional Motif

Abstract

a-Conotoxins are disulfide-richp eptides that target nicotinic acetylcholine receptors.Recently we identified several a-conotoxins that also modulate voltage-gated calcium channels by acting as Gp rotein-coupled GABA B receptor (GABA B R) agonists.T hese a-conotoxins are promising drug leads for the treatment of chronic pain. To elucidate the diversity of a-conotoxins that act through this mechanism, we synthesized and characterized aset of peptides with homology to a-conotoxins knownt oi nhibit high voltage-activated calcium channels via GABA B Ra ctivation. Remarkably,a ll disulfide isomers of the active a-conotoxins Pu1.2 and Pn1.2, and the previously studied Vc1.1 showed similar levels of biological activity.S tructure determination by NMR spectroscopyh elped us identify as implified biologically active eight residue peptide motif containing asingle disulfide bond that is an excellent lead molecule for developing anew generation of analgesic peptide drugs.

A mouse model of endometriosis that displays vaginal, colon, cutaneous, and bladder sensory comorbidities

“…The visceromotor response (VMR) is a nociceptive brainstem reflex consisting of the contraction of the abdominal muscles in response to noxious distension of hollow organs such as the vagina 53‐55 and the colorectum 56‐62 . We recorded the VMR to vaginal distension (VD) or colorectal distension (CRD) as an objective measurement of vaginal and colonic sensitivity to pain, respectively, in fully conscious animals 41,47,48,53‐55,63 .…”

“…The visceromotor response (VMR) is a nociceptive brainstem reflex consisting of the contraction of the abdominal muscles in response to noxious distension of hollow organs such as the vagina [53][54][55] and the colorectum. [56][57][58][59][60][61][62] We recorded the VMR to vaginal distension (VD) or colorectal distension (CRD) as an objective measurement of vaginal and colonic sensitivity to pain, respectively, in fully conscious animals. 41,47,48,[53][54][55]63 VMR of mice with fully developed endometriosis (weeks 8-10 after uterine horn fragment transplant) was compared with the VMR of Sham animals (weeks 8-10 after Sham fat transplant).…”

Marine Origin Ligands of Nicotinic Receptors: Low Molecular Compounds, Peptides and Proteins for Fundamental Research and Practical Applications

“…However, a second target of α-conotoxins Vc1.1 and RgIA GABA B receptors was identified (as well as for some other α-conotoxins [ 192 ]) and a different, more complex, mechanism of analgesic action was proposed through potent inhibition of N-type calcium channels via GABA B receptor activation. The role of cholinergic and GABA B -ergic systems in the analgesic action of these conopeptides is still being discussed and is reflected in numerous experimental studies and reviews (see, for example, [ 184 , 193 , 194 ]).…”