{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T04:20:58Z","timestamp":1783743658725,"version":"3.55.0"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2020,7,10]],"date-time":"2020-07-10T00:00:00Z","timestamp":1594339200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Male Contraceptive Initiative","award":["A2018-303"],"award-info":[{"award-number":["A2018-303"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,8,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Sympathetically mediated contractions of smooth muscle cells in the vasa deferentia are mediated by neuronally released adenosine 5\u2032-triphosphate (ATP) and noradrenaline, which stimulate P2X1-purinoceptors and \u03b11A-adrenoceptors, respectively. This process is crucial for sperm transport, as demonstrated in knockout mouse studies where simultaneous genetic deletion of P2X1-purinoceptors and \u03b11A-adrenoceptors resulted in male infertility. We hypothesize that dual pharmacological antagonism of these two receptors could inhibit sperm transport sufficiently to provide a novel nonhormonal method of male contraception. To generate a suitable P2X1-purinoceptor antagonist, substituents were introduced on the phenyl moiety of 2-phenyl-5,6,7,8-tetrahydroquinoxaline to create a series of analogues that were tested for P2X1-purinoceptor antagonism in isolated preparations of rat vas deferens. Novel compounds were initially screened for their ability to attenuate contractile responses to electrical field stimulation (EFS: 60\u00a0V, 0.5\u00a0ms, 0.2\u00a0Hz). The addition of polar substituents to the meta, but not ortho, position markedly increased the inhibition of contractions, as did the addition of both polar and aliphatic substituents to the para position. Di-substituted compounds were also synthesized and tested, resulting in a compound 31 (2-hydroxy, 4-fluoro), which exhibited the greatest potency, with an IC50 of 14\u00a0\u03bcM (95% confidence limits: 12\u201316\u00a0\u03bcM). Additionally, compound 31 noncompetitively antagonized contractions mediated by exogenously administered \u03b1\u00df-methylene ATP (10\u00a0nM\u201330\u00a0\u03bcM) but had no inhibitory effect on contractions mediated by exogenously administered noradrenaline (30\u00a0nM\u2013100\u00a0\u03bcM) or acetylcholine (30\u00a0nM\u2013100\u00a0\u03bcM). These results have contributed to a structure\u2013activity relationship profile for the P2X1-purinoceptor that will inform future designs of more potent antagonists.<\/jats:p>","DOI":"10.1093\/biolre\/ioaa117","type":"journal-article","created":{"date-parts":[[2020,7,10]],"date-time":"2020-07-10T11:54:21Z","timestamp":1594382061000},"page":"323-332","source":"Crossref","is-referenced-by-count":4,"title":["Synthesis of 2-phenyl-5,6,7,8-tetrahydroquinoxaline derivatives and screening for P2X1-purinoceptor antagonist activity in isolated preparations of rat vas deferens, for translation into a male contraceptive\u2020"],"prefix":"10.1093","volume":"103","author":[{"given":"Mitch","family":"Mathiew","sequence":"first","affiliation":[{"name":"Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belinda M","family":"Dennis","sequence":"additional","affiliation":[{"name":"Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Felix","family":"Bennetts","sequence":"additional","affiliation":[{"name":"Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N N Eunice","family":"Su","sequence":"additional","affiliation":[{"name":"Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nghi","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antony","family":"Botteon","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan B","family":"Baell","sequence":"additional","affiliation":[{"name":"Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabatino","family":"Ventura","sequence":"additional","affiliation":[{"name":"Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria. Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,7,10]]},"reference":[{"key":"2020093001145607200_ref1","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/j.contraception.2010.03.016","article-title":"Acceptability of contraception for men: A review","volume":"82","author":"Glasier","year":"2010","journal-title":"Contraception"},{"key":"2020093001145607200_ref2","first-page":"500","volume-title":"Management of Common Problems in Obstetrics and Gynecology","author":"Taylor","edition":"5th"},{"key":"2020093001145607200_ref3","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1093\/humrep\/15.3.646","article-title":"Would women trust their partners to use a male pill?","volume":"15","author":"Glasier","year":"2000","journal-title":"Human Reprod"},{"key":"2020093001145607200_ref4","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1016\/j.cell.2012.07.027","article-title":"Contraception for men: A breakthrough new approach","volume":"150","author":"Bremner","year":"2012","journal-title":"Cell"},{"key":"2020093001145607200_ref5","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.contraception.2012.08.016","article-title":"New approaches to male non-hormonal contraception","volume":"87","author":"Nya-Ngatchou","year":"2013","journal-title":"Contraception"},{"key":"2020093001145607200_ref6","first-page":"667","article-title":"Male contraception: Another holy grail","volume":"150","author":"Murdoch","year":"2014","journal-title":"Bioorg Med Chem Letters"},{"key":"2020093001145607200_ref7","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1093\/humrep\/15.3.637","article-title":"Potential impact of hormonal male contraception: Crosscultural implications for development of novel preparations","volume":"15","author":"Martin","year":"2000","journal-title":"Hum Reprod"},{"key":"2020093001145607200_ref8","doi-asserted-by":"crossref","first-page":"208","DOI":"10.5694\/j.1326-5377.2002.tb04374.x","article-title":"Will Australian men use male hormonal contraception? 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