{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:34:48Z","timestamp":1760150088688,"version":"build-2065373602"},"reference-count":62,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T00:00:00Z","timestamp":1696377600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003359","name":"Generalitat Valenciana","doi-asserted-by":"publisher","award":["PROMETEO\/2021\/031"],"award-info":[{"award-number":["PROMETEO\/2021\/031"]}],"id":[{"id":"10.13039\/501100003359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012818","name":"Comunidad de Madrid","doi-asserted-by":"publisher","award":["IND2017\/BMD7673"],"award-info":[{"award-number":["IND2017\/BMD7673"]}],"id":[{"id":"10.13039\/100012818","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Spanish Ministerio de Ciencia e Innovaci\u00f3n (cofunded by FEDER, una manera de hacer Europa)","award":["RTI2018-097189-B-C21, RTI2018-097189-B-C22, PID2021-126423OB-C21 and PID2021-126423OB-C22"],"award-info":[{"award-number":["RTI2018-097189-B-C21, RTI2018-097189-B-C22, PID2021-126423OB-C21 and PID2021-126423OB-C22"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The protein transient receptor potential melastatin type 8 (TRPM8), a non-selective, calcium (Ca2+)-permeable ion channel is implicated in several pathological conditions, including neuropathic pain states. In our previous research endeavors, we have identified \u03b2-lactam derivatives with high hydrophobic character that exhibit potent and selective TRPM8 antagonist activity. This work describes the synthesis of novel derivatives featuring C-terminal amides and diversely substituted N\u2032-terminal monobenzyl groups in an attempt to increase the total polar surface area (TPSA) in this family of compounds. The primary goal was to assess the influence of these substituents on the inhibition of menthol-induced cellular Ca2+ entry, thereby establishing critical structure\u2013activity relationships. While the substitution of the tert-butyl ester by isobutyl amide moieties improved the antagonist activity, none of the N\u2032-monobencyl derivatives, regardless of the substituent on the phenyl ring, achieved the activity of the model dibenzyl compound. The antagonist potency of the most effective compounds was subsequently verified using Patch-Clamp electrophysiology experiments. Furthermore, we evaluated the selectivity of one of these compounds against other members of the transient receptor potential (TRP) ion channel family and some receptors connected to peripheral pain pathways. This compound demonstrated specificity for TRPM8 channels. To better comprehend the potential mode of interaction, we conducted docking experiments to uncover plausible binding sites on the functionally active tetrameric protein. While the four main populated poses are located by the pore zone, a similar location to that described for the N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide (AMTB) antagonist cannot be discarded. Finally, in vivo experiments, involving a couple of selected compounds, revealed significant antinociceptive activity within a mice model of cold allodynia induced by oxaliplatin (OXA).<\/jats:p>","DOI":"10.3390\/ijms241914894","type":"journal-article","created":{"date-parts":[[2023,10,4]],"date-time":"2023-10-04T11:58:57Z","timestamp":1696420737000},"page":"14894","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["\u03b2-Lactam TRPM8 Antagonists Derived from Phe-Phenylalaninol Conjugates: Structure\u2013Activity Relationships and Antiallodynic Activity"],"prefix":"10.3390","volume":"24","author":[{"given":"Cristina","family":"Mart\u00edn-Escura","sequence":"first","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica (IQM-CSIC), 28006 Madrid, Spain"},{"name":"Alodia Farmac\u00e9utica SL, 28108 Alcobendas, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4922-5345","authenticated-orcid":false,"given":"M. \u00c1ngeles","family":"Bonache","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica (IQM-CSIC), 28006 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessy A.","family":"Medina","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica (IQM-CSIC), 28006 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8035-0179","authenticated-orcid":false,"given":"Alicia","family":"Medina-Peris","sequence":"additional","affiliation":[{"name":"IDiBE, Universidad Miguel Hern\u00e1ndez, 03202 Elche, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7797-4688","authenticated-orcid":false,"given":"Jorge","family":"De Andr\u00e9s-L\u00f3pez","sequence":"additional","affiliation":[{"name":"IDiBE, Universidad Miguel Hern\u00e1ndez, 03202 Elche, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6906-8108","authenticated-orcid":false,"given":"Sara","family":"Gonz\u00e1lez-Rodr\u00edguez","sequence":"additional","affiliation":[{"name":"IDiBE, Universidad Miguel Hern\u00e1ndez, 03202 Elche, Spain"},{"name":"Facultad de Medicina, Instituto Universitario de Oncolog\u00eda del Principado de Asturias (IUOPA), Universidad de Oviedo, Juli\u00e1n Claver\u00eda 6, 33006 Oviedo, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Kerselaers","sequence":"additional","affiliation":[{"name":"Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, VIB Center for Brain and Disease Research, KU Leuven, Herestraat 49 Box 802, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5412-8611","authenticated-orcid":false,"given":"Gregorio","family":"Fern\u00e1ndez-Ballester","sequence":"additional","affiliation":[{"name":"IDiBE, Universidad Miguel Hern\u00e1ndez, 03202 Elche, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5526-5821","authenticated-orcid":false,"given":"Thomas","family":"Voets","sequence":"additional","affiliation":[{"name":"Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, VIB Center for Brain and Disease Research, KU Leuven, Herestraat 49 Box 802, 3000 Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2973-6607","authenticated-orcid":false,"given":"Antonio","family":"Ferrer-Montiel","sequence":"additional","affiliation":[{"name":"IDiBE, Universidad Miguel Hern\u00e1ndez, 03202 Elche, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2741-1427","authenticated-orcid":false,"given":"Asia","family":"Fern\u00e1ndez-Carvajal","sequence":"additional","affiliation":[{"name":"IDiBE, Universidad Miguel Hern\u00e1ndez, 03202 Elche, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8833-4328","authenticated-orcid":false,"given":"Rosario","family":"Gonz\u00e1lez-Mu\u00f1iz","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica (IQM-CSIC), 28006 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,4]]},"reference":[{"doi-asserted-by":"crossref","unstructured":"Kashio, M., and Tominaga, M. (2022). TRP channels in thermosensation. Curr. Opin. Neurobiol., 75.","key":"ref_1","DOI":"10.1016\/j.conb.2022.102591"},{"key":"ref_2","first-page":"998","article-title":"Temperature sensing","volume":"270","author":"Tominaga","year":"2019","journal-title":"Igaku No Ayumi"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"jcs258372","DOI":"10.1242\/jcs.258372","article-title":"TRP channels in health and disease at a glance","volume":"134","author":"Yue","year":"2021","journal-title":"J. Cell Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1007\/978-94-007-0265-3_36","article-title":"Expression and physiological roles of TRP channels in smooth muscle cells","volume":"704","author":"Guibert","year":"2011","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/j.tips.2019.07.004","article-title":"Targeting TRP Channels\u2014Valuable Alternatives to Combat Pain, Lower Urinary Tract Disorders, and Type 2 Diabetes?","volume":"40","author":"Voets","year":"2019","journal-title":"Trends Pharmacol. Sci."},{"doi-asserted-by":"crossref","unstructured":"Gonzalez-Cobos, J.C., Zhang, X., Motiani, R.K., Harmon, K.E., and Trebak, M. (2012). TRPs to Cardiovascular Disease, Springer.","key":"ref_6","DOI":"10.1007\/978-1-62703-095-3_1"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"10006","DOI":"10.1021\/acs.jmedchem.6b00305","article-title":"Transient Receptor Potential Melastatin 8 Channel (TRPM8) Modulation: Cool Entryway for Treating Pain and Cancer","volume":"59","year":"2016","journal-title":"J. Med. Chem."},{"doi-asserted-by":"crossref","unstructured":"Izquierdo, C., Martin-Martinez, M., Gomez-Monterrey, I., and Gonzalez-Muniz, R. (2021). TRPM8 Channels: Advances in Structural Studies and Pharmacological Modulation. Int. J. Mol. Sci., 22.","key":"ref_8","DOI":"10.3390\/ijms22168502"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1677\/erc.1.01093","article-title":"TRPM8 in prostate cancer cells: A potential diagnostic and prognostic marker with a secretory function?","volume":"13","author":"Zhang","year":"2006","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/nature05910","article-title":"The menthol receptor TRPM8 is the principal detector of environmental cold","volume":"448","author":"Bautista","year":"2007","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1523\/JNEUROSCI.3976-07.2008","article-title":"Visualizing cold spots: TRPM8-expressing sensory neurons and their projections","volume":"28","author":"Dhaka","year":"2008","journal-title":"J. Neurosci."},{"doi-asserted-by":"crossref","unstructured":"De Caro, C., Cristiano, C., Avagliano, C., Bertamino, A., Ostacolo, C., Campiglia, P., Gomez-Monterrey, I., La Rana, G., Gualillo, O., and Calignano, A. (2019). Characterization of new TRPM8 modulators in pain perception. Int. J. Mol. Sci., 20.","key":"ref_12","DOI":"10.3390\/ijms20225544"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"17448069211002008","DOI":"10.1177\/17448069211002009","article-title":"Cold pain sensitivity is associated with single-nucleotide polymorphisms of PAR2\/F2RL1 and TRPM8","volume":"17","author":"Soeda","year":"2021","journal-title":"Mol. Pain"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1213337","DOI":"10.3389\/fphar.2023.1213337","article-title":"Molecular determinants of TRPM8 function: Key clues for a cool modulation","volume":"14","author":"Pertusa","year":"2023","journal-title":"Front. Pharmacol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/978-3-540-34891-7_20","article-title":"TRPM8","volume":"Volume 179","author":"Voets","year":"2007","journal-title":"Handbook of Experimental Pharmacology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1007\/978-3-642-54215-2_22","article-title":"TRPM8","volume":"Volume 222","author":"Almaraz","year":"2014","journal-title":"Handbook of Experimental Pharmacology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"173312","DOI":"10.1016\/j.ejphar.2020.173312","article-title":"TRPM8 channels: A review of distribution and clinical role","volume":"882","author":"Liu","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1540\/jsmr.58.11","article-title":"The TRPM8 channel as a potential therapeutic target for bladder hypersensitive disorders","volume":"58","author":"Aizawa","year":"2022","journal-title":"J. Smooth Muscle Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"690858","DOI":"10.3389\/fnmol.2021.690858","article-title":"Oxaliplatin depolarizes the IB4- dorsal root ganglion neurons to drive the development of neuropathic pain through TRPM8 in mice","volume":"14","author":"Wu","year":"2021","journal-title":"Front. Mol. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2101717","DOI":"10.1002\/advs.202101717","article-title":"Rational Design of a Modality-Specific Inhibitor of TRPM8 Channel against Oxaliplatin-Induced Cold Allodynia","volume":"8","author":"Aierken","year":"2021","journal-title":"Adv. Sci."},{"doi-asserted-by":"crossref","unstructured":"Fakih, D., Baudouin, C., Goazigo, A.R.-L., and Parsadaniantz, S.M. (2020). TRPM8: A therapeutic target for neuroinflammatory symptoms induced by severe dry eye disease. Int. J. Mol. Sci., 21.","key":"ref_21","DOI":"10.3390\/ijms21228756"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1159\/000350107","article-title":"Down-Regulation of TRPM8 in Pulmonary Arteries of Pulmonary Hypertensive Rats","volume":"31","author":"Liu","year":"2013","journal-title":"Cell. Physiol. Biochem."},{"doi-asserted-by":"crossref","unstructured":"Naumov, D.E., Kotova, O.O., Gassan, D.A., Sugaylo, I.Y., Afanas\u2019eva, E.Y., Sheludko, E.G., and Perelman, J.M. (2021). Effect of TRPM8 and TRPA1 Polymorphisms on COPD Predisposition and Lung Function in COPD Patients. J. Pers. Med., 11.","key":"ref_23","DOI":"10.3390\/jpm11020108"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1093\/abbs\/gmy033","article-title":"Inhibition of transient receptor potential melastatin 8 alleviates airway inflammation and remodeling in a murine model of asthma with cold air stimulus","volume":"50","author":"Liu","year":"2018","journal-title":"Acta Biochim. Biophys. Sin."},{"doi-asserted-by":"crossref","unstructured":"Szallasi, A. (2023). ThermoTRP Channel Expression in Cancers: Implications for Diagnosis and Prognosis (Practical Approach by a Pathologist). Int. J. Mol. Sci., 24.","key":"ref_25","DOI":"10.3390\/ijms24109098"},{"doi-asserted-by":"crossref","unstructured":"Gonzalez-Muniz, R., Bonache, M.A., Martin-Escura, C., and Gomez-Monterrey, I. (2019). Recent progress in TRPM8 modulation: An update. Int. J. Mol. Sci., 20.","key":"ref_26","DOI":"10.3390\/ijms20112618"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8186","DOI":"10.1021\/acs.jmedchem.8b00518","article-title":"Discovery of TRPM8 Antagonist (S)-6-(((3-Fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)carbamoyl)nicotinic Acid (AMG 333), a Clinical Candidate for the Treatment of Migraine","volume":"61","author":"Horne","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1021\/ml500479v","article-title":"Discovery of a selective TRPM8 antagonist with clinical efficacy in cold-related pain","volume":"6","author":"Andrews","year":"2015","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1080\/13543784.2020.1825680","article-title":"Investigational drugs in early phase clinical trials targeting thermotransient receptor potential (thermoTRP) channels","volume":"29","year":"2020","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"S161","DOI":"10.1016\/j.ejps.2017.06.009","article-title":"A cross-species translational pharmacokinetic-pharmacodynamic evaluation of core body temperature reduction by the TRPM8 blocker PF-05105679","volume":"109S","author":"Gosset","year":"2017","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1186\/1744-8069-8-36","article-title":"Transient receptor potential melastatin 8 (TRPM8) channels are involved in body temperature regulation","volume":"8","author":"Gavva","year":"2012","journal-title":"Mol. Pain"},{"doi-asserted-by":"crossref","unstructured":"Thapa, D., Barrett, B., Argunhan, F., and Brain, S.D. (2022). Influence of Cold-TRP Receptors on Cold-Influenced Behaviour. Pharmaceuticals, 15.","key":"ref_32","DOI":"10.3390\/ph15010042"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"10766","DOI":"10.1038\/s41598-017-10913-x","article-title":"Synthesis, high-throughput screening and pharmacological characterization of \u03b2-lactam derivatives as TRPM8 antagonists","volume":"7","author":"Bonache","year":"2017","journal-title":"Sci. Rep."},{"doi-asserted-by":"crossref","unstructured":"Bonache, M.\u00c1., Llabr\u00e9s, P.J., Mart\u00edn-Escura, C., De la Torre-Mart\u00ednez, R., Medina-Peris, A., Butr\u00f3n, L., G\u00f3mez-Monterrey, I., Roa, A.M., Fern\u00e1ndez-Ballester, G., and Ferrer-Montiel, A. (2021). Phenylalanine-derived \u03b2-lactam trpm8 modulators. Configuration effect on the antagonist activity. Int. J. Mol. Sci., 22.","key":"ref_34","DOI":"10.3390\/ijms22052370"},{"doi-asserted-by":"crossref","unstructured":"Martin-Escura, C., Medina-Peris, A., Spear, L.A., de la Torre Martinez, R., Olivos-Ore, L.A., Barahona, M.V., Gonzalez-Rodriguez, S., Fernandez-Ballester, G., Fernandez-Carvajal, A., and Artalejo, A.R. (2022). \u03b2-Lactam TRPM8 Antagonist RGM8-51 Displays Antinociceptive Activity in Different Animal Models. Int. J. Mol. Sci., 23.","key":"ref_35","DOI":"10.3390\/ijms23052692"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"14154","DOI":"10.1038\/s41598-020-70691-x","article-title":"Highly functionalized \u03b2-lactams and 2-ketopiperazines as TRPM8 antagonists with antiallodynic activity","volume":"10","author":"Bonache","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.ejphar.2006.07.026","article-title":"Mu and kappa opioid receptor agonists antagonize icilin-induced wet-dog shaking in rats","volume":"547","author":"Werkheiser","year":"2006","journal-title":"Eur. J. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2719","DOI":"10.1021\/jm901137j","article-title":"New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from Screening Libraries and for Their Exclusion in Bioassays","volume":"53","author":"Baell","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1021\/ol070533d","article-title":"Exceptional Stereoselectivity in the Synthesis of 1,3,4-Trisubstituted 4-Carboxy \u03b2-Lactam Derivatives from Amino Acids","volume":"9","year":"2007","journal-title":"Org. Lett."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1021\/acsmedchemlett.1c00001","article-title":"Structural and in Vitro Functional Characterization of a Menthyl TRPM8 Antagonist Indicates Species-Dependent Regulation","volume":"12","author":"Journigan","year":"2021","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3790","DOI":"10.1038\/s41467-020-17582-x","article-title":"Molecular mechanisms underlying menthol binding and activation of TRPM8 ion channel","volume":"11","author":"Xu","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"eaav9334","DOI":"10.1126\/science.aav9334","article-title":"Structural basis of cooling agent and lipid sensing by the cold-activated TRPM8 channel","volume":"363","author":"Yin","year":"2019","journal-title":"Science"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2683","DOI":"10.1111\/bph.14994","article-title":"Functional expression and pharmacological modulation of TRPM3 in human sensory neurons","volume":"177","author":"Vangeel","year":"2020","journal-title":"Br. J. Pharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1021\/cn100094b","article-title":"Le ASIC3 channels in multimodal sensory perception","volume":"2","author":"Li","year":"2011","journal-title":"ACS Chem. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"775","DOI":"10.2174\/1389450120666190131114244","article-title":"Insight into Pain Modulation: Nociceptors Sensitization and Therapeutic Targets","volume":"20","author":"Khan","year":"2019","journal-title":"Curr. Drug Targets"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2803","DOI":"10.1523\/JNEUROSCI.2303-22.2023","article-title":"Endogenous inflammatory mediators produced by injury activate TRPV1 and TRPA1 nociceptors to induce sexually dimorphic cold pain that is dependent on TRPM8 and GFRa3","volume":"43","author":"Yang","year":"2023","journal-title":"J. Neurosci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"40427","DOI":"10.1074\/jbc.M110.176966","article-title":"Dynamic control of glutamatergic synaptic input in the spinal cord by muscarinic receptor subtypes defined using knockout mice","volume":"285","author":"Chen","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"407","DOI":"10.4196\/kjpp.2016.20.4.407","article-title":"Involvement of spinal muscarinic and serotonergic receptors in the anti-allodynic effect of electroacupuncture in rats with oxaliplatin-induced neuropathic pain","volume":"20","author":"Lee","year":"2016","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"ref_49","first-page":"G637","article-title":"Toward an effective peripheral visceral analgesic: Responding to the national opioid crisis","volume":"314","author":"Camilleri","year":"2018","journal-title":"Am. J. Physiol."},{"key":"ref_50","first-page":"18","article-title":"Chemotherapy-induced neurotoxicity: The value of neuroprotective strategies","volume":"70","author":"Beijers","year":"2012","journal-title":"Neth. J. Med."},{"doi-asserted-by":"crossref","unstructured":"Rimola, V., Osthues, T., Koenigs, V., Geisslinger, G., and Sisignano, M. (2021). Oxaliplatin causes transient changes in TRPM8 channel activity. Int. J. Mol. Sci., 22.","key":"ref_51","DOI":"10.3390\/ijms22094962"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1021\/acschemneuro.9b00404","article-title":"Structure-Based Design of Novel Biphenyl Amide Antagonists of Human Transient Receptor Potential Cation Channel Subfamily M Member 8 Channels with Potential Implications in the Treatment of Sensory Neuropathies","volume":"11","author":"Journigan","year":"2020","journal-title":"ACS Chem. Neurosci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"9672","DOI":"10.1021\/acs.jmedchem.0c00816","article-title":"Exploration of TRPM8 Binding Sites by \u03b2-Carboline-Based Antagonists and Their In Vitro Characterization and In Vivo Analgesic Activities","volume":"63","author":"Bertamino","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1126\/science.aan4325","article-title":"Structure of the cold- and menthol-sensing ion channel TRPM8","volume":"359","author":"Yin","year":"2018","journal-title":"Science"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1126\/science.aax6672","article-title":"Structural insights into TRPM8 inhibition and desensitization","volume":"365","author":"Diver","year":"2019","journal-title":"Science"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.neulet.2016.12.063","article-title":"Cellular permeation of large molecules mediated by TRPM8 channels","volume":"639","author":"McCoy","year":"2017","journal-title":"Neurosci. Lett."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock and AutoDockTools: Automated docking with selective receptor flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1999","DOI":"10.1002\/jcc.10349","article-title":"A point-charge force field for molecular mechanics simulations of proteins based on condensed-phase quantum mechanical calculations","volume":"24","author":"Duan","year":"2003","journal-title":"J. Comput. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"5293","DOI":"10.1021\/acs.jcim.1c00743","article-title":"Assembly of Biomolecular Gigastructures and Visualization with the Vulkan Graphics API","volume":"61","author":"Ozvoldik","year":"2021","journal-title":"J. Chem. Inf. Model."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"W443","DOI":"10.1093\/nar\/gkv315","article-title":"PLIP: Fully automated protein-ligand interaction profiler","volume":"43","author":"Salentin","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.neuron.2011.02.051","article-title":"TRPM3 Is a Nociceptor Channel Involved in the Detection of Noxious Heat","volume":"70","author":"Vriens","year":"2011","journal-title":"Neuron"},{"unstructured":"Gonz\u00e1lez-Mu\u00f1iz, R., P\u00e9rez de Vega, M.J., Bonache de Marcos, M.\u00c1., Ferrer-Montiel, A., Fern\u00e1ndez-Carvajal, A., and de la Torre-Martinez, R. Heterocyclic Compounds as TRPM8 Channel Antagonists and Uses Thereof. WO 2017005950 12 January 2017. Available online: http:\/\/hdl.handle.net\/10261\/176227.","key":"ref_62"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/19\/14894\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:05:20Z","timestamp":1760130320000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/19\/14894"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,10,4]]},"references-count":62,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2023,10]]}},"alternative-id":["ijms241914894"],"URL":"https:\/\/doi.org\/10.3390\/ijms241914894","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,10,4]]}}}