52 research outputs found
Structural requirements for ligands of the delta-opioid receptor
The delta-opioid receptor is sensitive to ligand geometry. In order to assist the synthesis of new delta-selective opioid ligands, the structure elements of delta-selective opioid ligands necessary for their effective binding were investigated. The automated docking procedure with a flexible ligand was used to simulate the binding of 17 delta-selective ligands to the delta-receptor. It was found that voluminous N-alkyl groups reduce the binding potency of naltrindole derivatives by preventing the ligands from adopting the preferred conformation in the receptor. This was confirmed by enantiospecific binding of chiral compounds where only one enantiomer adopts the naltrindole-like preferred conformation in the binding pocket. Voluminous groups replacing the hydroxyl group in the 3-hydroxybenzyl fragment of naltrindole analogs reduce the binding potency due to unfavorable steric interactions with the receptor. The two diastereoisomers of the potent delta-opioid ligand SNC80 confirmed the preferred binding conformation and the major receptor-ligand interactions
Stereoselektivno slobodnoradikalsko fenilsulfenilovanje neaktiviranog Ī“-ugljenikovog atoma
A stereoselective free radical introduction of a phenylthio group onto a nonactivated methyl group in the 8-position, adjacent to a prochiral carbon atom, was achieved by photolysis of (-)-menthyl benzenesulfenate in the presence of hexabutylditin and (1R, 3R, 4S, 8S)-9-phenylthiomenthot (4) was obtained with 91 % optical purity. High stereoselectivity of the reaction was calculated (ab initio MP2/6-3 1G**) to be the consequence of the difference in the transition state eneregies (DeltaDeltaG(#) = 5.08 kJ/mol) favouring 4 relative to (1R,3R,4S,8R)-9-phenylthiomenthoI (5). The absolute configuration of a the new chiral carbon atom was confirmed by its correlation with the corresponding menthane-3,9-diol of known stereochemistry.Fotolizom (ā)-mentil-benzensulfenata u prisustvu heksabutil-dikalaja izvrÅ”eno je stereoselektivno uvoÄenje feniltio grupe na neaktiviranu metil grupu u Ī“-položaju koja je susedna prohiralnom ugljenikovom atomu i dobiven je (1R 3R, 4S, 8S)-9-feniltio-mentol (4) sa 91 % optiÄke ÄistoÄe. Visoka stereoselektivnost reakcije, potvrÄena raÄunom (ab initio MP2/6-21G**) posledica je razlike u energijama prelaznih stanja ĪĪG# = 5.08 kJ/mol) koja favorizuje nastajanje 4 u odnosu na (1R, 3R, 4S, 8R)-9-feniltio-mentol (5). Apsolutna konfiguracija novog hiralnog ugljenikovog atoma potvrÄena je korelacijom s odgovarajuÄim mentan-3,9-diolom poznate stereohemije
Optimizovana sinteza znaÄajnog farmaceutskog intermedijera metil 4-[(1-oksopropil)fenilamino]piperidin-4-karboksilata
An efficient synthesis of methyl 4-[(1-oxopropyl)phenylamino]piperidine-4-carboxylate (7) has been developed starting from 1-benzylpiperidin-4-one (1). The compound is a key intermediate in the synthesis of new generation, highly active narcotic analgesics, such as remifintanil, as well as the novel classes of fentanyl analogues. An optimized Strecker-type condensation of piperidone 1 with aniline and HCN yielded the anilino-nitrile 2(ā90%) which, upon selective hydrolysis with conc. H2SO4, gave the anilino-amide 3.After vigorous basic hydrolysis of 3, followed by acidification and successive treatment with SOCl2 and MeOH, the anilino-ester 5 was obtained (40ā45%, in 3 steps). N-Acylation of 5 with propionyl chloride yielded the anilido-ester 6(70ā80%) In the final step, the catalytic N-debenzylation of 6 was examined under various conditions and optimized to yield 7 in near quantitative yields.U ovom radu razvijena je efikasna sinteza metil 4-[(1-oksopropil)fenilamino]piperidin-4-karboksilata (7), prolazeÄi od 1-benzil piperidin-4-on-1 (1). Jedinjenje 7 je kljuÄni intermedijer u sintezi nove generacije visoko aktivnih narkotiÄkih analgetika, kao Å”to je remifentanil a takoÄe i novih klasa analoga fentanyla. U optimizovanoj Strecker-ovoj kondenzaciji priperidona 1 sa anilinom i HCN, dobijen je anilino-nitril 2 (ā90%) prinos Äijom je selektivnom hidrolizom pomoÄu konc. H2SO4 postao anilino-amid 3. Intenzivnom baznom hidrolizom ovog intermedijera, zakiÅ”eljavanjem a zatim sukcesivno reakcijom sa SOCl2 i MeOH sintetisan je anilino-estar 5 (ā40ā45% prinos u 3 faze). N-acelovanjem anilino-estra 5 sa propionil hloridom postao je anilido-estar 6 (ā70ā80% prinos). U poslednjom fazi sinteze izvrÅ”ena je optimizacija katalitiÄkog N-debenzilovanja anilido-estra 6 do finalnog proizvoda 7, u približno kvantitativnom prinosu
Supplementary material for the article: JevtiÄ, I. I.; DoÅ”en-MiÄoviÄ, L. I.; IvanoviÄ, E. R.; TodoroviÄ, N. M.; IvanoviÄ, M. D. Synthesis of Orthogonally Protected (Ā±)-3-Amino-4-Anilidopiperidines and (Ā±)-3- N -Carbomethoxyfentanyl. Synthesis (Germany) 2017, 49 (14), 3126ā3136. https://doi.org/10.1055/s-0036-1588985
Supporting information for: [https://doi.org/10.1055/s-0036-1588985]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2492
Supplementary data for the article: PopoviÄ-DjordjeviÄ, J.; StepanoviÄ, S.; DoÅ”en-MiÄoviÄ, L.; IvanoviÄ, E.; IvanoviÄ, M. D. High-Yielding Method for Preparation of Carbocyclic or N-Containing Heterocyclic Ī²-Keto Esters Using in Situ Activated Sodium Hydride in Dimethyl Sulphoxide. Green Chemistry Letters and Reviews 2016, 9 (1), 61ā68. https://doi.org/10.1080/17518253.2016.1145744
Supplementary material for: [https://doi.org/10.1080/17518253.2016.1145744]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/115
Supplementary data for the article: JevtiÄ, I. I.; DoÅ”en-MiÄoviÄ, L.; IvanoviÄ, E. R.; IvanoviÄ, M. D. Hofmann Rearrangement of Carboxamides Mediated by N-Bromoacetamide. Synthesis (Germany) 2016, 48 (10), 1550ā1560. https://doi.org/10.1055/s-0035-1561405
Supplementary material for: [https://doi.org/10.1055/s-0035-1561405]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1935
Supplementary data for the article: PopoviÄ-DjordjeviÄ, J.; StepanoviÄ, S.; DoÅ”en-MiÄoviÄ, L.; IvanoviÄ, E.; IvanoviÄ, M. D. High-Yielding Method for Preparation of Carbocyclic or N-Containing Heterocyclic Ī²-Keto Esters Using in Situ Activated Sodium Hydride in Dimethyl Sulphoxide. Green Chemistry Letters and Reviews 2016, 9 (1), 61ā68. https://doi.org/10.1080/17518253.2016.1145744
Supplementary material for: [https://doi.org/10.1080/17518253.2016.1145744]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/115
Ispitivanje neurotoksiÄnosti analoga fentanila kod pacova
This study aimed at evaluating the neurotoxicity of fentanyl analogs: (+/-)-cis-3-carbomethoxy fentanyl (C) and (+/-)-trans-3-carbomethoxy fentanyl (T) in rats. C and Tare less potent (2.4-3.1 and 8.4-12.3 times, respectively) than fentanyl (F) in producing both antinociception and morphine-like neurotoxic effects: loss of pinna reflex, Straub tail, impairment of motor coordination, catalepsy, loss of corneal reflex and loss of righting reflex. All of the effects tested were dose-dependent and they were abolished by pretreatment with naloxone, nonselective antagonist of opioid receptors, indicating that they are mediated via opioid receptors. Further, F, C and T exhibited similar relative potencies in producing all tested effects, indicating that similar receptors are involved in producing antinociceptive and neurotoxic effects, most probably of mu type. By using equiantinociceptive doses, C and T produced significantly shorter duration of both antinociception and neurotoxicity than F No significant differences between therapeutic indices for F, C and T were found, indicating that these compounds are equally safe and tolerable in respect to the neurotoxic effects tested. Neurotoxicity testing presented in this paper may be useful in studying the structure-activity relationship of opioid congeners.Cilj studije bio je da se ispita neurotoksiÄnost analoga fentanila: (Ā±)-cis-3-karbometoksi fentanila (C) i (Ā±)-trans-3-karbometoksi fentanil (T) kod pacova. C je oko 2,4-3,1, a T oko 8,4-12,3 puta manje potentan od fentanila u izazivanju antinocicepcije i morfinu-sliÄnih neurotoksiÄnih efekata u koje spadaju: refleks uÅ”ne Å”koljke, Straub-ov rep, poremeÄaj motorne koordinacije, katalepsija, gubitak kornealnog refleksa i gubitak refleksa uspravljanja. Svi ispitivani efekti su dozno-zavisni i bivaju poniÅ”teni ako se u pretretmanu primeni nalokson, neselektivni antagonist opioidnih receptora, Å”to ukazuje da se efekti odigravaju posredstvom opioidnih receptora. Dalje, F, C i T ispoljavaju sliÄnu relativnu jaÄinu u izazivanju ispitivanih efekata, Å”to ukazuje da su sliÄni receptori ukljuÄeni u mehanizam antinocicepcije i neurotoksiÄnih efekata, i to su najverovatnije Ī¼ receptori. Kad se primenjuju ekviantinociceptivne doze, C i T izazivaju znaÄajno kraÄe i antinociceptivno i neurotoksiÄno dejstvo od F. Nisu dokazane znaÄajne razlike u terapijskim indeksima izmeÄu F, C i T, Å”to ukazuje da su ovi lekovi jednako bezbedni i podnoÅ”ljivi kad su u pitanju ispitivani neurotoksiÄni efekti. Ispitivanje neurotoksiÄnosti prikazano u ovom radu može biti korisno u prouÄavanju odnosa izmeÄu strukture i aktivnosti hemijski srodnih opioida
Sinteza i preliminarni farmakoloŔki testovi recemskih cis i trans 3-alkilanaloga fentanila
A general five step method for the synthesis of 3-alkylfentanyl analogues (i.e. cis and trans 3-alkyl-4-anilidopiperidines 6.1-6.6) has been developed, The starting N-phenethyl-4-piperidone 1 was first converted into the cyclohexylimine derivative 2. alpha-deprotonated with butyllithium and die resulting imine anion efficiently monoalkylated with primary, and secondary alkyl halides. After mild acid hydrolysis. the obtained 3-alkyl-4-piperidones 3.1-3.6 were isolated in good yields (79-85%), then condensed with aniline to form imines 4.1-4.6. Subsequent reduction of the imines (LiAlH4/THF) yielded cis/trans mixtures of 3-alkyl-4-anilinopiperidines 5.1-5.6. Quantitative separation of the diastereoisomers by column chromatography of Al2O3 gave pure cis 5.1-5.6 (29-51% yield) and trans 5.1-5.6 (19-27% yield), with the cis/trans ratio in the range 7/3-6/4 . The synthesis was concluded by N-acylation of the purified 5.1-5.6, with propionyl chloride, to afford cis and trans 3-alkyl-4-anilidopiperidines 6.1-6.6 (approximate to 95% yield, as monooxalate salts). No enatioseparation was attempted at any stage. The relative cis/trans stereochemistry was provisionally assigned from the H-1-NMR spectra. Of the twelve synthesized 3-alkylfentanyls. ten compounds (two known and eight novel derivatives, all as the monooxalate salts) were preliminarily tested as analgesics in rats, comparing the potency to fentanyl. Except for the known (+/-)-cis-3-Me fentanyl 6.1cis. (8 x fentanyl), and the novel (+/-)-cis-3-Et fentanyl 6.2cis. (1.5 x fentanyl), all of the others were less active than fentanyl or inactive. Some tentative conclusions on the structure-activity relationship (SAR) in this series of derivatives have been made.Razvijen je opÅ”ti metod za sintezu 3-alkil analoga fentanila (tj. cis i trans 3-alkil-4-anilidopiperidina 6.1ā6.6) u pet faza. Polazni N-fenetil-4-piperidon 1 prvo je preveden u cikloheksiliminski derivat 2, Ī±-deprotonovan butillitijumom, a postali iminski anjon efikasno monoalkilovan primarnim i sekundarnim alkilhalogenidima. Posle blage kisele hidrolize, nastali 3-alkil-4-piperidoni 3.1ā3.6 izolovani su u dobrim prinosima (79ā85 %), zatim kondenzovani sa anilinom do imina 4.1ā4.6. Redukcijom ovih imina (LiAlH4/THF) dobijene su cis/trans smese 3-alkil-4-anilinopiperidina 5.1ā5.6. Kvantitativnim hromatografskim razdvajanjem dijastereoizomera na stubu Al2O3 izolovani su Äisti cis 5.1ā5.6 (prinos 29ā51 %) i trans 5.1ā5.6 (prinos 19ā27 %), gde je cis/trans odnos bio u opsegu 7/3ā6/4. Sinteza je zavrÅ”ena N-acilovanjem preÄiÅ”Äenih intermedijera 5.1ā5.6 pomoÄu propionil-hlorida, pri Äemu su postali cis i trans 3-alkil-4-anilidopiperidini 6.1ā6.6 (prinos _ 95 %, kao monooksalatne soli). Ni u jednoj fazi nije pokuÅ”ano razdvajanje enantiomera. Relativna, cis/trans, stereohemija preliminarno je odreÄena iz 1H-NMRspektra. Od dvanaest sintetisanih 3-alkil-fentanila, deset jedinjenja (dva poznata i osam novih, sva u obliku monookasalatnih soli) preliminarno su testirana kao analgetici na pacovima, poredeÄi aktivnost sa fentanilom.Osim poznatog (Ā±)-cis-3-Me fentanila 6.1 cis, (8 x fentanil), i novog (Ā±)-cis-3-Et fentanila 6.2 cis, (1,5 x fentanil), svi ostali bili su manje aktivni ili neaktivni. Izvedeni su odreÄeni, preliminarni zakljuÄci u vezi odnosa strukture i aktivnosti u ovoj seriji derivata
Supplementary material for the article: JevtiÄ, I. I.; DoÅ”en-MiÄoviÄ, L. I.; IvanoviÄ, E. R.; TodoroviÄ, N. M.; IvanoviÄ, M. D. Synthesis of Orthogonally Protected (Ā±)-3-Amino-4-Anilidopiperidines and (Ā±)-3- N -Carbomethoxyfentanyl. Synthesis (Germany) 2017, 49 (14), 3126ā3136. https://doi.org/10.1055/s-0036-1588985
Supporting information for: [https://doi.org/10.1055/s-0036-1588985]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/2492
- ā¦