Abstract
(−)-cis-N-Normetazocine represents a rigid scaffold able to mimic the tyramine moiety of endogenous opioid peptides, and the introduction of different N-substituents influences affinity and efficacy of respective ligands at MOR (mu opioid receptor), DOR (delta opioid receptor), and KOR (kappa opioid receptor). We have previously identified LP1, a MOR/DOR multitarget opioid ligand, with an N-phenylpropanamido substituent linked to (−)-cis-N-Normetazocine scaffold. Herein, we report the synthesis, competition binding and calcium mobilization assays of new compounds 10–16 that differ from LP1 by the nature of the N-substituent. In radioligand binding experiments, the compounds 10–13, featured by an electron-withdrawing or electron-donating group in the para position of phenyl ring, displayed improved affinity for KOR (Ki = 0.85–4.80 μM) in comparison to LP1 (7.5 μM). On the contrary, their MOR and DOR affinities were worse (Ki = 0.18–0.28 μM and Ki = 0.38–1.10 μM, respectively) with respect to LP1 values (Ki = 0.049 and 0.033 μM). Analogous trends was recorded for the compounds 14–16, featured by indoline, tetrahydroquinoline, and diphenylamine functionalities in the N-substituent. In calcium mobilization assays, the compound 10 with a p-fluorophenyl in the N-substituent shared the functional profile of LP1 (pEC50MOR = 7.01), although it was less active. Moreover, the p-methyl- (11) and p-cyano- (12) substituted compounds resulted in MOR partial agonists and DOR/KOR antagonists. By contrast, the derivatives 13–15 resulted as MOR antagonists, and the derivative 16 as a MOR/KOR antagonist (pKBMOR = 6.12 and pKBKOR = 6.11). Collectively, these data corroborated the critical role of the N-substituent in (−)-cis-N-Normetazocine scaffold. Thus, the new synthesized compounds could represent a template to achieve a specific agonist, antagonist, or mixed agonist/antagonist functional profile.
Highlights
IntroductionSemi-synthetic, and synthetic opioid ligands [1,2,3,4], featured with different structural scaffolds, exert their action following recognition of three different opioid receptors, namely mu, Natural, semi-synthetic, and synthetic opioid ligands [1,2,3,4], featured with different structural scaffolds, exert their action following recognition of three different opioid receptors, namely mu, delta, aanndd kkaappppaaooppioioididrerceecpeptotorsrs(M(MOORR, D, DOOR,Ra,nadndKOKRO,Rre, srpeescpteivcteilvye)l,yw),hwichicahreamreemmbeemrsbeorfsthoef tlahregelasrugpeesrufapmeriflyamofilGy pofroGteipnrcooteuipnlecdourepclepdtorersce(GptPoCrsR(sG) [P5C] tRhsa)t [c5o]utphlaettocoGuip/olemtoemGbie/ros amnedmobtheersr apnrodteointhsetro rpergoutelaintes stiognraelginugla. tEendsioggneanloinugs. ligEandsogoefntohuesse lriegcaenpdtosrsofartehoespeioridecpepeptotirdsesargeenoepriaolildy pcheaprtaidcteesrizgeednebrayllythechhairgahcltyercizoendserbvyedthNe -theirgmhilnyalcotentsrearpveepdtidNic-tesremquineanlceteTtryarp–eGplyti–dGiclys–ePqhueen[6c]e, Tayltrh–oGulgyh–Gthlye–MPhOeR[-6s]e,leacltihvoeuegnhdothgeenMouOsRp-seeplteicdteivs,eeennddoomgoernpohuisn-p1e(pEtMid-e1s,, Teynrd–oPmroo–rTprhpi–nP-h1e(–ENMH-12), Taynrd–Proen–Tdropm–Porhpeh–iNn-H22) (aEnMd-2e,ndoTmyro–rPprhoi–nP-h2e–(EPMhe-–2N, HT2y)r, –Prhoa–dPhea–Phde–ifNfeHre2n)t, hasedquaendcieffere[7n]t. s(−e)q-uciesn-Nce-N[7o]r.m(e−ta)z-coicsi-nNe-,Nroersmuelttianzgocfinroem, resaulptirnoggrferossmivea psrimogprleisfisciavteiosnimopflifimcaotriponhinoef msokreplehtoinne, srekpelreetsoenn,tsreaprriegsidenstcsaafforligdiadbslecatfofosludppabolret tthoespuhpepnoorlticthriengphaenndotlhice rbiansgicannidtrothgeenbainsiac cnointrfoogremnatiniona cmoinmfoicrkminagtiothnemtyimraimckiinnegmthoeiettyyraomf oinpeiomidopieetpytiodfeosp[i8o]i.dInpesepvtiedreasl i[n8]v.eIsntigsaevtieornasl,itnhveepstiivgoattaiol nros,lethoef pthiveostuablsrtoitlueeonfttahtethsue bbsatsiticuennittroagt ethnehbasaseimc neritgreodge[9n–h13a]s. eInmdeeregde,dth[9e–N13-s]u. bInstditeueedn,ttnhaetuNr-esuinbfslutietunecnest nafaftiunriteyi,nsfleuleecnticveistya,ffianditya,csteivleictytivtoitwy,aarndds alclttivhirteyetopwioaridsreacllepthtroeresoupbitoyipderse. ceptor subtypes.Wee hhaavve pprreevviioouussllyy rreeppoorrtteed tthhee ssyynntthheesis aannd pphhaarrmmacological characterization of different series of ((−−))--cciiss--NN--nnoorrmmeettaazzoocciinnee--bbaasseeddlliiggaannddss[[1144]]
The compound 10 with a p-fluorophenyl in the N-substituent shared the functional profile of LP1, it was less active
Only compound 10 shares a functional profile with LP1, it was less active, and it binds MOR and DOR with a Ki in the micromolar range. p-Methyl- (11) and p-cyano- (12) derivatives display comparable functional profile, resulting in MOR partial agonists and DOR/KOR antagonists. Their MOR potencies were higher than compound 10, but lower than LP1. These results enabled us to recognize how the presence of bulkier substituents and their electronic effect in the N-phenylpropanamido chain could be a stringent feature for opioid receptors efficacy profile
Summary
Semi-synthetic, and synthetic opioid ligands [1,2,3,4], featured with different structural scaffolds, exert their action following recognition of three different opioid receptors, namely mu, Natural, semi-synthetic, and synthetic opioid ligands [1,2,3,4], featured with different structural scaffolds, exert their action following recognition of three different opioid receptors, namely mu, delta, aanndd kkaappppaaooppioioididrerceecpeptotorsrs(M(MOORR, D, DOOR,Ra,nadndKOKRO,Rre, srpeescpteivcteilvye)l,yw),hwichicahreamreemmbeemrsbeorfsthoef tlahregelasrugpeesrufapmeriflyamofilGy pofroGteipnrcooteuipnlecdourepclepdtorersce(GptPoCrsR(sG) [P5C] tRhsa)t [c5o]utphlaettocoGuip/olemtoemGbie/ros amnedmobtheersr apnrodteointhsetro rpergoutelaintes stiognraelginugla. tEendsioggneanloinugs. ligEandsogoefntohuesse lriegcaenpdtosrsofartehoespeioridecpepeptotirdsesargeenoepriaolildy pcheaprtaidcteesrizgeednebrayllythechhairgahcltyercizoendserbvyedthNe -theirgmhilnyalcotentsrearpveepdtidNic-tesremquineanlceteTtryarp–eGplyti–dGiclys–ePqhueen[6c]e, Tayltrh–oGulgyh–Gthlye–MPhOeR[-6s]e,leacltihvoeuegnhdothgeenMouOsRp-seeplteicdteivs,eeennddoomgoernpohuisn-p1e(pEtMid-e1s,, Teynrd–oPmroo–rTprhpi–nP-h1e(–ENMH-12), Taynrd–Proen–Tdropm–Porhpeh–iNn-H22) (aEnMd-2e,ndoTmyro–rPprhoi–nP-h2e–(EPMhe-–2N, HT2y)r, –Prhoa–dPhea–Phde–ifNfeHre2n)t, hasedquaendcieffere[7n]t. s(−e)q-uciesn-Nce-N[7o]r.m(e−ta)z-coicsi-nNe-,Nroersmuelttianzgocfinroem, resaulptirnoggrferossmivea psrimogprleisfisciavteiosnimopflifimcaotriponhinoef msokreplehtoinne, srekpelreetsoenn,tsreaprriegsidenstcsaafforligdiadbslecatfofosludppabolret tthoespuhpepnoorlticthriengphaenndotlhice rbiansgicannidtrothgeenbainsiac cnointrfoogremnatiniona cmoinmfoicrkminagtiothnemtyimraimckiinnegmthoeiettyyraomf oinpeiomidopieetpytiodfeosp[i8o]i.dInpesepvtiedreasl i[n8]v.eIsntigsaevtieornasl,itnhveepstiivgoattaiol nros,lethoef pthiveostuablsrtoitlueeonfttahtethsue bbsatsiticuennittroagt ethnehbasaseimc neritgreodge[9n–h13a]s. eInmdeeregde,dth[9e–N13-s]u. bInstditeueedn,ttnhaetuNr-esuinbfslutietunecnest nafaftiunriteyi,nsfleuleecnticveistya,ffianditya,csteivleictytivtoitwy,aarndds alclttivhirteyetopwioaridsreacllepthtroeresoupbitoyipderse. ceptor subtypes.Wee hhaavve pprreevviioouussllyy rreeppoorrtteed tthhee ssyynntthheesis aannd pphhaarrmmacological characterization of different series of ((−−))--cciiss--NN--nnoorrmmeettaazzoocciinnee--bbaasseeddlliiggaannddss[[1144]]. Semi-synthetic, and synthetic opioid ligands [1,2,3,4], featured with different structural scaffolds, exert their action following recognition of three different opioid receptors, namely mu, Natural, semi-synthetic, and synthetic opioid ligands [1,2,3,4], featured with different structural scaffolds, exert their action following recognition of three different opioid receptors, namely mu, delta, aanndd kkaappppaaooppioioididrerceecpeptotorsrs(M(MOORR, D, DOOR,Ra,nadndKOKRO,Rre, srpeescpteivcteilvye)l,yw),hwichicahreamreemmbeemrsbeorfsthoef tlahregelasrugpeesrufapmeriflyamofilGy pofroGteipnrcooteuipnlecdourepclepdtorersce(GptPoCrsR(sG) [P5C] tRhsa)t [c5o]utphlaettocoGuip/olemtoemGbie/ros amnedmobtheersr apnrodteointhsetro rpergoutelaintes stiognraelginugla. TThheesseeddaattaa ddeemmoonnssttrraatteedd that the introduction of tthhee aacceettaammiiddoossppaacceerrininththeebabsaiscicnintritorgoegnenwwasadsedtreitmriemnetnaltaflorfoMr OMRO, RD,ODRO, aRn, danKdOKRObRindbindg.inBgy. b2,e6n-mzaeztohcainno-3-3(2-bHe)n-yzal]z-oNc-ipnh-3e(n2yHlp)-ryolp]-aNn-apmheidney,lpFriogpuarneam1)i,dfee,atuFreigdurweith 1a), N-pfehaetnuyrelpdropawniathmidoa sNu-bpshteitnuyelnptr,orpeasnualtmedidionshuibgshtiMtueOnRt, arensdulstiegdnifinchaingthDMOORRbaindisnignciofiucpanletdDtOoRabMinOdRin/gDcOouRpalegdontoisat mMuOlRtit/aDrOgeRt pargoofinleis,tcomnusilsttietanrtgwetithpriotsfislieg,ncifioncasnistteannttinwoictihceiptstivseigenffieficctainntnaoncticineopctivcepatnivdepefrfseicstenint pnaoicnicerpativme oadnedlspe[1rs5i–s1te7n].t paItinhraast amlsoodehlsig[h1l5i–g1h7te].dIttheas iamlspoorhtiagnhcleighintedthteheNi-msupbosrttiatunceentinofthae sNe-csounbdsatirtyueanmt oidfea fsoercothnedaorpyioaimdidreecfeoprtothreinotpeiroaicdtiroencsep[1to4r],inwtehrialecttihoensp[r1e4s]e,nwcehiolef taheteprtrieasreyncaemoidf ae ltedrtiatorypaomoirdeKliedvatloupeso,ormKaiivnalyluetos,wmaardinslyMtoOwRa.rdMsoMreOoRve. rM, othreovcreirt,icthale crorilteicaolf rtohle oafrtohme atriocmraintigc irningthienNth-ephNe-npyhlepnroyplparnoapmanidamo isdpoacsepracweraswaassseassesds.edS.aStautruartaetdedchchaianins smmaaddeewwoorrssee tthhee receptor binding interaction, the cyclohexyl ring retained a signifificant MOR aaffifinniittyy [[1144]]. Prove MOR and DOR affinity [20].
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