871
Views
0
CrossRef citations to date
0
Altmetric
Review

Fentanyl-Related Compounds and Derivatives: Current Status and Future Prospects for Pharmaceutical Applications

&
Pages 385-412 | Published online: 17 Mar 2014

References

  • Woolf CJ , BorsookD, KoltzenburgM, Mechanism-based classifications of pain and analgesic drug discovery. In: Pain: Current Understanding, Emerging Therapies and Novel Approaches to Drug Discovery. Bountra C, Munglani R, Schmidt WK (Eds). Marcel Dekker, NY, USA, 1–8 (2003).
  • Woodcock J , WitterJ, DionneRA. Stimulating the development of mechanism-based, individualized pain therapies.Nat. Rev. Drug Disc.6(9), 703–710 (2007).
  • Kissin I . The Development of new analgesics over the past 50 years: a lack of real breakthrough drugs.Anesth. Analg.110(3), 780–789 (2010).
  • Grape S , SchugSA, LauerS, SchugBS. Formulations of fentanyl for the management of pain.Drugs70(1), 57–72 (2010).
  • Nelson L . Schwaner R. Transdermal fentanyl: pharmacology and toxicology.J. Med. Toxicol.5(4), 230–241 (2009).
  • Jeal W , BenfieldP. Transdermal fentanyl: a review of its pharmacological properties and therapeutic efficacy in pain control.Drugs53(1), 109–138 (1997).
  • Darwish M , MessinaJ. Clinical pharmacology of buccal tablet for the treatment of breakthrough pain.Exp. Rev. Clin. Pharmacol.1(1), 39–47 (2008).
  • Taylor DR . Fentanyl buccal tablet: rapid relief from breakthrough pain.Exp. Opin. Pharmacother.8(17), 3043–3051 (2007).
  • Davis MP . Fentanyl for breakthrough pain: a systematic review.Exp. Rev. Neurotherapeut.11(8), 1197–1216 (2011).
  • Mystakidou K , PanagiotouI, GouliamosA. Fentanyl nasal spray for the treatment of cancer pain.Exp. Opin. Pharmacother.12(10), 1653–1659 (2011).
  • Casy AF , HassanMM, SimmondsB, StaniforthD. Structure–activity relations in analgesics based on 4-anilinopiperidine.J. Pharm. Pharmacol.21(7), 434–440 (1969).
  • Bagley JR , KudzmaLV, LalindeNLet al. Evolution of the 4-anilidopiperidine class of opioid analgesics. Med. Res. Rev. 11(4), 403–436 (1991).
  • Vuckovic S , ProstranM, IvanovicMet al. Fentanyl analogs: structure–activity-relationship study. Curr. Med. Chem. 16(19), 2468–2474 (2009).
  • Yadav P , ChauhanJS, GanesanKet al. Synthetic methodology and structure activity relationship study of N-[1-(2-phenylethyl)-piperidin-4-yl]-propionamides. Pharm. Sinica 1(3), 126–139 (2010).
  • Yaksh TL , NoueihedRY, DurantPAC. Studies of the pharmacology and pathology of intrathecally administered 4-anilinopiperidine analogs and morphine in the rat and cat.Anesthesiol.64(1), 54–66 (1986).
  • Planas E . Fentanyl pharmacological characteristics.Dolor.15(1), 7–12 (2000).
  • Poklis A . Fentanyl: a review for clinical and analytical toxicologist.J. Tox. Clin. Tox.33(5), 439–447 (1995).
  • Andrews CJH , Prys-RobertsC. Fentanyl – a review.Clinics Anaesthesiol.1(1), 97–122 (1983).
  • Mather LE . Clinical pharmacokinetics of fentanyl and its newer derivatives.Clin. Pharmacokinet.8(5), 422–446 (1983).
  • Massey J . Stop the pain: fentanyl is a viable alternative to morphine.JEMS36(8), 54–57 (2011).
  • Pasero C . Fentanyl for acute pain management.J. Perianesth. Nurs.20(4), 279–84 (2005).
  • Peng PW , SandlerAN. A review of the use of fentanyl analgesia in the management of acute pain in adults.Anesthesiol.90(2), 576–599 (1999).
  • Grass JA . Fentanyl: clinical use as postoperative analgesic–epidural/intrathecal route.J. Pain Symptom Manage.7(7), 419–430 (1992).
  • Stanley TH . Fentanyl.J. Pain Symptom Manage.29(5S), S67–S71 (2005).
  • Stanley TH . The history and development of the fentanyl series.J. Pain Symptom Manage.7(3 Suppl.), S3–S7 (1992).
  • Casy AF , ParfittRT. Opioid Analgesics: Chemistry and Receptors. Springer, NY, USA (1986).
  • Lenz GR , EvansSM, WaltersDE, HopfingerAJ. Opiates. Academic Press, MA, USA (1986).
  • Lednicer D . Central Analgetics – Chemistry and Pharmacology of Drugs, A Series of Monographs Vol. 1. Wiley-Interscience, NY, USA (1982).
  • Buschmann H , ChristophT, FriderichsE, MaulC. Analgesics: From Chemistry and Pharmacology to Clinical Application. Wiley-VCH, Weinheim, Germany (2002).
  • DeStevens G . Analgetics – Medicinal Chemistry, A Series of Monographs, Vol. 5. Academic Press, NY, USA (1965).
  • Hellerbach J , SchniderO, BesendorfH, PellmontB. Synthetic Analgesics, Part IIA: Morphinans, Organic Chemistry. Vol. VIII. Pergamon Press, London, UK (1966).
  • Nathan B , EddyNB, MayEL. Synthetic Analgesics, Part IIB: Benzomorphans - International Series of Monographs on Organic Chemistry Vol. 8. Pergamon Press, London, UK (1966).
  • Janssen PAJ . Synthetic Analgesics, Part I: Diphenylpropylamines - International Series of Monographs on Organic Chemistry Vol. 3. Pergamon Press, London, UK (1960).
  • Sawynok J , CowanA. Novel Aspects of Pain Management: Opioids and Beyond. Wiley-Liss, NY, USA (1999).
  • Lemke TH , WilliamsDA, RocheVF, ZitoSW. Foye’s Principles of Medicinal Chemistry. Lippincott Williams and Wilkins, WoltersKluwer Health, PA, USA (2013).
  • Abraham DJ , RotellaDP. Burger’s Medicinal Chemistry and Drug Discovery 7th Edition. John Wiley and Sons, Inc., NJ, USA (2010).
  • Teiggle DJ , TaylorJB. Comprehensive Medicinal Chemistry II. Elsevier Science, London, UK (2006).
  • Thomas G . Fundamentals of Medicinal Chemistry. Wiley-Blackwell, NJ, USA (2003).
  • Vardanyan RS , HrubyVJ. Synthesis of Essential Drugs. Elsevier, Amsterdam, The Netherlands (2006).
  • Block J , BealeJM. Wilson and Gisvold’s Textbook of Organic Medicinal and Pharmaceutical Chemistry 11th Edition. Lippincott Williams and Wilkins, PA, USA (2003).
  • Galemmo RA Jr, Janssens FE, Lewi PJ et al. In Memoriam: Dr Paul AJ Janssen (1926–2003). J. Med. Chem.48(6), 1686 (2005).
  • Black J . A personal perspective on Dr Paul Janssen.J. Med. Chem.48(6), 1687–1688 (2005).
  • Van Gestel S , SchuermansV. Thirty-three years of drug discovery and research with Dr Paul Janssen.Drug Dev. Res.8(1–4), 1–13 (1986).
  • Stanley TH , EganTD, Van Aken H. A tribute to Dr Paul AJ Janssen: entrepreneur extraordinaire, innovative scientist, and significant contributor to anesthesiology. Anesth. Analgesia106(2), 451–462 (2008).
  • Janssen PAJ , JageneauAH, DemoenPJAet al. Compounds related to Pethidine. I. Mannich bases derived from norpethidine and acetophenones. J. Med. Pharm. Chem. 1, 105–120 (1959).
  • Janssen PAJ , JageneauAHM, DemoenPJAet al. Compounds related to pethidine. II. Mannich bases derived from various esters of 4-carboxy-4-phenylpiperidine and acetophenones. J. Med. Pharm. Chem. 1, 309–317 (1959).
  • Janssen PAJ , JageneauAH, DemoenPJAet al. Compounds related to pethidine. III. Basic ketones derived from norpethidine. J. Med. Pharm. Chem. 2, 271–280 (1960).
  • Wright WB Jr, Brabander HJ, Hardy RA Jr. Synthetic analgesics. III. Basic anilides and carbanilates containing the phenylalkyl moiety. J. Org. Chem.26, 485–490 (1961).
  • Janssen PAJ , GardockiJF: US3141823 (1964).
  • Janssen PAJ : FR M2430 (1964).
  • Janssen PA , NiemegeersCJ, DonyJG. The inhibitory effect of fentanyl and other morphine-like analgesics on the warm water induced tail withdrawl reflex in rats.Arzneimittelforschung13, 502–507 (1963).
  • Janssen PAJ : US3164600 (1965).
  • Janssen PAJ . The development of new synthetic narcotics. In: Opioids in Anesthesia II. Estafanous FG (Ed.). Butterworth-Heinemann, MA, USA, 37–44 (1983).
  • Van Bever WFM , NiemegeersCJE, SchellekensKHL, JanssenPAJ. N-4-substituted 1-(2-arylethyl)-4-piperidinyl-N-phenylpropanamides, a novel series of extremely potent analgesics with unusually high safety margin. Arzneimittelforschung26(8), 1548–1551 (1976).
  • Gardocki JF , YelnoskyJ. Some of the pharmacologic actions of fentanyl citrate and droperidol.Toxicol. Appl. Pharmacol.6(1), 48–62 (1964).
  • Chrubasik J , WustH, Schulte-MontingJet al. Relative analgesic potency of epidural fentanyl, alfentanil, and morphine in treatment of postoperative pain. Anestheziol. 68(6), 929–933 (1988).
  • Reynolds L , RauckR, WebsterLet al. Relative analgesic potency of fentanyl and sufentanil during intermediate-term infusions in patients after long-term opioid treatment for chronic pain. Pain 110(1–2), 182–188 (2004).
  • Planas E . Fentanyl pharmacological characteristics.Dolor15(1), 7–12 (2000).
  • Barutell C , RiberaMV, MartinezPet al. Fentanyl. Dolor 19(2), 98–104 (2004).
  • Andrews CJH , Prys-RobertsC. Fentanyl – a review.Clin. Anaesthesiol.1(1), 97–122 (1983).
  • Schulz R , WusterM, RubiniP, HerzA. Functional opiate receptors in the guinea-pig ileum: their differentiation by means of selective tolerance development.J. Pharmacol. Exp. Ther.219, 547–550 (1981).
  • Mohamed YH , EssawiMYH, PortoghesePS. Synthesis and evaluation of 1- and 2-substituted fentanyl analogs for opioid activity.J. Med. Chem.26(3), 348–352 (1983).
  • Magnan J , PatersonSJ, TavaniA, KosterlitzW. The binding spectrum of narcotic analgesic drugs with different agonist and antagonist properties.Arch. Pharmacol.319(3), 197–205 (1982).
  • Maguire P , TsaiN, KamalJet al. Pharmacological profiles of fentanyl analogs at µ, δ and κ opiate receptors. Eur. J. Pharmacol. 213(2), 219–225 (1992).
  • Jin WQ , PatersonSJ, KosterlitzHW, CasyAF. Interactions of some 4-anilino-piperidines and 4-phenylpiperidines with the µ-, δ- and κ-binding sites.Life Sci.33(Suppl. 1), 251–253 (1983).
  • Boas RA , VilligerJW. Clinical actions of fentanyl and buprenorphine. The significance of receptor binding.Brit. J. Anaesth.57(2), 192–196 (1985).
  • Lehmann KA , WeskiC, HungerL. Biotransformation of fentanyl. II. Acute drug interactions in rats and men.Anaesthesist31(5), 221–227 (1982).
  • Lehmann KA , HungerL, BrandtK, DaubD. Biotransformation of fentanyl. III. Effect of chronic drug administration on distribution, metabolism and excretion in the rat.Anaesthesist32(4), 165–173 (1983).
  • Jonczyk A , JawdosiukM, MakoszaM, CzyzewskiJ. Search for a new method for synthesis of the analgesic agent “Fentanyl”.Przeml. Chem.57(3), 131–134 (1978).
  • Zee S -H, Wang W-K. A new process for the synthesis of fentanyl. J. Chin. Chem. Soc.27(4), 147–149 (1980).
  • Casy AF , HassanMMA. Analgesically active basic anilides: stereospecificity and structure of the basic group.J. Pharm. Pharmacol.19(1), 17–24 (1967).
  • Wright WB Jr, Hardy RA Jr. Synthetic analgesics. IV. Synthesis of enantiomers of basic anilides containing the phenalkyl moiety. J. Med. Chem.6, 128–130 (1963).
  • Ivanovic MD , MicovicIV, VuckovicSet al. The synthesis and pharmacological evaluation of (±)-2,3-seco-fentanyl analogs. J. Serb. Chem. Soc. 69(11), 955–968 (2004).
  • Helsley GC , LunsfordCD, WelsteadWJ Jr et al. Synthesis and analgetic activity of some 1-substituted 3-pyrrolidinylanilides and dihydrobenz-oxazinones. J. Med. Chem.12(4), 583–586 (1969).
  • Finney ZG , RileyTN. 4-Anilidopiperidine analgesics. 3. 1-Substituted 4-(propananilido)-perhydroazepines as ring-expanded analogs.J. Med. Chem.23(8), 895–899 (1980).
  • DeRuiter J , AndurkarS, RileyTNet al. Investigation of the synthesis and analgesic activity of 1-substituted 4-(propananilido)perhydroazepines. J. Het. Chem. 29(4), 779–786 (1992).
  • Bagley JR , RileyTN. Synthesis and conformational analysis of isomeric 3-propan-anilidotropanes.J. Het. Chem.14(4), 599–602 (1977).
  • Riley TN , BagleyJR. 4-Anilidopiperidine analgesics. 2. A study of the conformational aspects of the analgesic activity of the 4-anilidopiperidines utilizing isomeric N-substituted 3-(propananilido)nor-tropane analogs.J. Med. Chem.22(10), 1167–1171 (1979).
  • Fernandez MJ , HuertasRM, GalvezEet al. Synthesis, and structural, conformational and pharmacological studies of new fentanyl derivatives of the norgranatane system. J. Chem. Soc. Perkin Trans. 2 4, 687–695 (1992).
  • Law S -J, Lewis DH, Borne RF. Synthesis and stereochemical analysis of isomeric N-substituted 5- and 6-propanilido-2-azabicyclo[2.2.2]octanes. J. Het. Chem.15(2), 273–280 (1978).
  • Borne RF , Law S-J, Kapeghian JC, Masten LW. Evaluation of 2-azabicyclo[2.2.2]octane analogs of 4-anilidopiperidine analgesics. J. Pharm. Sci.69(9), 1104–1106 (1980).
  • Riley TN , HaleDB, WilsonMC. 4-Anilidopiperidine analgesics. I. Synthesis and analgesic activity of certain ring-methylated, 1-substituted 4-propananilidopiperidines.J. Pharmaceut. Sci.62(6), 983–986 (1973).
  • Riley TN , HaleDB: US3923992 (1975).
  • Vartanyan SA , VartanyanRS, ZhamagortsyanVNet al. SU736583 (1985).
  • Vartanian RS , AirapetyanGK, MarkaryanEAet al. SU1100848 (1984).
  • Vartanyan RS , MartirosyanVO, VartanyanSAet al. Synthesis and analgesic activity of 4-anilides of 1-substituted 2,5-dimethylpiperidines. Khim. Farm. Zh. 23(5), 562–565 (1989).
  • Karapetyan AA , Struchkov YuT, Timofeeva TV et al. Structure and activity of phenaridine stereoisomers. Khim. Farm. Zh.23(5), 565–572 (1989).
  • Vartanyan RS , MartirosyanVO, VartanyanSAet al. Stereochemistry and biological properties of the new narcotic analgesic phenaridine. Khim. Farm. Zh. 23(5), 573–578 (1989).
  • Van Bever WFM , NiemegeersCJE, JanssenPAJ. Synthetic analgesics. Synthesis and pharmacology of the diastereoisomers of N-[3-methyl-1-(2-phenylethyl)-4-piperidyl]-N-phenyl-propanamide and N-[3-methyl-1-(1-methyl-2-phenylethyl)-4-piperidyl]-N-phenyl-propanamide. J. Med. Chem.17(10), 1047–1051 (1974).
  • Ivanovic MD , MicovicIV, VuckovicSet al. The synthesis and preliminary pharmacological evaluation of the racemic cis and trans 3-alkylfentanyl analogs. J. Serb. Chem. Soc. 69(7), 511–526 (2004).
  • Karapetyan HA , Struchkov YuT, MartirosyanVOet al. The structure of analgesics of the 4-anilinopiperidine series. III. Structure of 1(e)-(2-phenethyl)-2(e),5(e)-dimethyl-4(e)-(N-propionylanilino)piperidine bisulfate. Zh. Strukt. Kh.31(2), 141–145 (1990).
  • Karapetyan AA , TimofeyevaTV, Struchkov YuT, Martirosyan VO. Conformation of the 4-(propionylanilino) pharmacophore in stereoisomers of the 2,5-dimethyl derivative of phentanyl (phenaridine). Khim. Farm. Zh.26(9–10), 25–28 (1992).
  • Dzhingozyan VK , MartirosyanVO, KarapetyanAAet al. Effect of 2-methyl substituent on the conformation of 1-(2-phenylethyl) pharmacophore in 4-propanoyl(phenyl)piperidines. Khim. Farm. Zh. 30(8), 40–42 (1996).
  • Lalinde NL , MoliterniJ, SpencerHK: US4939161 (1990).
  • Prost M : DE2656678 (1977).
  • Micovic IV , IvanovicMD, VuckovicSMet al. The synthesis and preliminary pharmacological evaluation of 4-methyl fentanyl. Bioorg. Med Chem. Lett. 10(17), 2011–2014 (2000).
  • Kudzma LV , SevernakSA, BenvengaMJet al. 4-phenyl- and 4-heteroaryl-4-anilido-piperidines. A novel class of analgesic and anesthetic agents. J. Med. Chem. 32(12), 2534–2542 (1989).
  • Lin B -S, Kudzma LV, Spencer HK: US4791120 (1988).
  • Kudzma LV , SpencerHK: US4801615 (1989).
  • Van Daele PG , De BruynMF, BoeyJMet al. Synthetic analgesics: N-(1-[2-arylethyl]-4-substituted 4-piperidinyl) N-arylalkanamides. Arzneimittelforschung26(8), 1521–31 (1976).
  • Janssen PAJ , Van Daele GHP: US4179569 (1979).
  • Thompson RG , Menking,D, ValdesJJ. Opiate receptor binding properties of carfentanil.Chem. Res. Dev. Eng. Cent. Report (1987).
  • Van Bever WFM , NiemegeersCJE, SchellekensKHL, JanssenPAJ. N-4-substituted 1-(2-arylethyl)-4-piperidinyl-N-phenylpropanamides, a novel series of extremely potent analgesics with unusually high safety margin. Arzneimittelforschung26(8), 1548–1551 (1976).
  • Niemegeers CJ , SchellekensKH, Van Bever WF, Janssen PA. Sufentanil, a very potent and extremely safe intravenous morphine-like compound in mice, rats and dogs. Arzneimittelforschung26(8), 1551–1556 (1976).
  • Janssens F , TorremansJ, JanssenPAJ. Synthetic 1,4-disubstituted 1,4-dihydro-5H-tetrazol-5-one derivatives of fentanyl: alfentanil (R 39209), a potent, extremely short-acting narcotic analgesic.J. Med. Chem.29(11), 2290–2297 (1986).
  • Niemegeers CJE , JanssenPAJ. Alfentanil (R 39 209) – a particularly short-acting intravenous narcotic analgesic in rats.Drug Dev. Res.1(1), 83–88 (1981).
  • Bagley JR , ThomasSA, RudoFGet al. New 1-(heterocyclylalkyl)-4-(propionanilido)-4-piperidinyl methyl ester and methylene methyl ether analgesics. J. Med. Chem. 34(2), 827–841 (1991).
  • Janssen PAJ ,Van Daele GHP: US4179569 (1979).
  • Kiricojevic VD , IvanovicMD, MicovicIVet al. An optimized synthesis of a key pharmaceutical intermediate: methyl 4-[(1-oxopropyl) phenylamino]piperidine-4-carboxylate. J. Serb. Chem. Soc. 67(12), 793–802 (2002).
  • Srimurugan S , MuruganK, ChenC. A facile method for preparation of [2H3]-sufentanil and its metabolites. Chem. Pharm. Bull.57(12), 1421–1424 (2009).
  • Henriksen G , PlatzerS, MartonJet al. Syntheses, biological evaluation, and molecular modeling of 18F-labeled 4-anilidopiperidines as µ-opioid receptor imaging agents. J. Med. Chem. 48(24), 7720–7732 (2005).
  • Feldman PL , JamesMK, BrackeenMFet al. Design, synthesis, and pharmacological evaluation of ultrashort- to long-acting opioid analgesics. J. Med. Chem. 34(7), 2202–2206 (1991).
  • Feldman PL , JamesMK, BrackeenMF, JohnsonMR, LeightonH: EP383.579 (1990).
  • Cui Y , PanL, NingY, ZhangK, ZhengJ. Analgesic effect and time-effect relation of remifentanil.Zhongguo Yaowu Yilaixing Zazhi12(4), 268–269, 283 (2003).
  • Nora FS , FortisE, AparecidaF. Remifentanil: do we need another opioid?Rev. Bras. Anestesiol.51(2), 146–159 (2001).
  • Battershill AJ , KeatingGM. Remifentanil: a review of its analgesic and sedative use in the intensive care unit.Drugs66(3), 365–385 (2006).
  • Scott LJ , PerryCM. Remifentanil. A review of its use during the induction and maintenance of general anaesthesia.Drugs65(13), 1793–1823 (2005).
  • Beers R , CamporesiE. Remifentanil update: clinical science and utility.CNS Drugs52(6), 1095–1104 (2004).
  • Wilhelm W , WrobelM, KreuerS, LarsenR. Remifentanil. An update,Anaesthesist52(6), 473–494 (2003).
  • Rosow CE . An overview of remifentanil.Anesth. Analg.89(4 Suppl.), S1–S3 (1999).
  • Peacock JE . Remifentanil clinical studies.Drugs Today33(9), 619–626 (1997).
  • Patel SS , SpencerCM. Remifentanil.Drugs52(3), 417–427 (1996).
  • Buerkle HDS , Van Aken H. Remifentanil: a novel, short-acting, µ-opioid. Anesth. Analg.83(3), 646–651 (1996).
  • James MK . Remifentanil and anesthesia for the future.Exp. Opin. Invest. Drugs3(4), 331–340 (1994).
  • Floegel O , WeiglU: WO2010000282 (2010).
  • Cheng BK -M, Halvachs RE: WO2008066708 (2008).
  • Cheng B : WO2008045192 (2008).
  • Jacob M , KillgoreJK: WO2001040184 (2001).
  • Malaquin S , Jida,M, Gesquiere J-C et al. Ugi reaction for the synthesis of 4-aminopiperidine-4-carboxylic acid derivatives. Application to the synthesis of carfentanil and remifentanil. Tetr. Lett.51(22), 2983–2985 (2010).
  • Colapret JA , DiamantidisG, SpencerHKet al. Synthesis and pharmacological evaluation of 4,4-disubstituted piperidines. J. Med. Chem. 32(5), 968–974 (1989).
  • Casy AF , HuckstepMR. Structure-activity studies of fentanyl.J. Pharm. Pharmacol.40(9), 605–608 (1988).
  • Peters D , EriksenBL, MunroGN, OestergaardE: WO2009077584 (2009).
  • Bagley JR , WynnRL, RudoFGet al. New 4-(heteroanilido)piperidines, structurally related to the pure opioid agonist fentanyl, with agonist and/or antagonist properties. J. Med. Chem. 32, 663–671 (1989).
  • Wynn RL , BagleyJR, SpencerHK, SpauldingTC. Evaluation of the morphine reversal actions and antinociceptive activity of a new class of opiate antagonists structurally related to fentanyl.Drug Develop. Res.22(2), 189–195 (1991).
  • Vartanian RS , VartanianSA, MartirosyanVOet al. SU1139125 (1984).
  • Jagerovic N , CanoC, ElgueroJet al. Long-acting fentanyl analogs: synthesis and pharmacology of N-(1-phenylpyrazolyl)-N-(1-phenylalkyl-4-piperidyl)propanamides. Bioorg. Med. Chem. 10(3), 817–827 (2002).
  • Giron R , AbaloR, GoicoecheaCet al. Synthesis and opioid activity of new fentanyl analogs. Life Sci. 71(9), 1023–3104 (2002).
  • Jimeno ML , AlkortaI, CanoCet al. Fentanyl and its analog N-(1-phenylpyrazol-3-yl)-N-[1-(2-phenylethyl)-4-piperidyl]propanamide: 1H- and 13C-NMR spectroscopy, x-ray crystallography, and theoretical calculations. Chem. Pharm. Bull. 51(8), 929–934 (2003).
  • Goicoechea C , SanchezE,Cano C et al. Analgesic activity and pharmacological characterization of N-[1-phenylpyrazol-3-yl]-N-[1-(2-phenethyl)-4-piperidyl] propenamide, a new opioid agonist acting peripherally. Eur. J. Pharmacol.595(1–3), 22–29 (2008).
  • Montero A , GoyaP, JagerovicNet al. Guanidinium and aminoimidazolinium derivatives of N-(4-piperidyl)propanamides as potential ligands for µ opioid and I2-imidazoline receptors: synthesis and pharmacological screening. Bioorg. Med. Chem. 10(4), 1009–1018 (2002).
  • Dardonville C , JagerovicN, CalladoLF, MeanaJJ. Fentanyl derivatives bearing aliphatic alkaneguanidinium moieties: a new series of hybrid molecules with significant binding affinity for mu-opioid receptors and I2-imidazoline binding sites. Bioorg. Med. Chem. Lett.14(2), 491–493 (2004).
  • Lalinde NL , MoliterniJ, SpencerHK: US4994471 (1991).
  • Micovic IV , IvanovicMD, VuckovicSet al. 3-Carbomethoxy fentanyl: synthesis, pharmacology and conformational analysis. Het. Comm. 4(2), 171–179 (1998).
  • Vuckovic S , ProstranM, IvanovicMet al. Antinociceptive activity of novel fentanyl analog iso-carfentanyl in rats. Jpn. J. Pharmacol. 84, 188–195 (2000).
  • Essawi MYH , PortoghesePS. Synthesis and evaluation of 1- and 2-substituted fentanyl analogs for opioid activity.J. Med. Chem.26(3), 348–352 (1983).
  • Micovic IV , RoglicGM, IvanovicMDet al. The synthesis of lactam analogs of fentanyl. J. Chem. Soc. Perkin Trans. 1(16), 2041–2050 (1996).
  • Micovic IV , RoglicGM, IvanovicMDet al. The synthesis of 3,3-dimethylfentanyl and its lactam analog. J. Serb. Chem. Soc. 61(10), 849–857 (1996).
  • Klein W , BackW, MutschlerE. Potential analgesics. 3. 1-(4-piperidinyl)-2-indolinones and -3,4-dihydrocarbostyrils.Arch. Pharm.307(5), 360–366 (1974).
  • Walker GN , SmithRT, WeaverBN. Synthesis of new 3-(pyridylmethylene)-, 3-(pyridylmethyl)-, 3-(piperidylmethyl)-, and 3-(β-alkylaminoethyl)-2-indolinones. The reduction of isoindogenides, nitro compounds, and pyridines in a series of 2-indolinones.J. Med. Chem.8(5), 626–637 (1965).
  • Lobbezoo MW , SoudijnW, Van Wijngaarden I. Opiate receptor interaction of compounds derived from or structurally related to fentanyl. J. Med. Chem.24(7), 777–782 (1981).
  • Vartanyan RS , MartirosyanVO, VlasenkoEV, OvasapyanAA. Synthesis and biological activity of 1-substituted benzimidazole and benztriazole derivatives.Khim. Farm. Zh.16(8), 947–951 (1982).
  • Kudzma LV , EvansSM, TurnbullSPet al. Octahydro-1,2,3,4,4a,5,11,11a-pyrido3,4-c1,5benzoxazepines conformationally restricted fentanyl analogs. Bioorg. Med. Chem. Lett. 5(11), 1177–1182 (1995).
  • Van Dyke JW Jr, Havera HJ, Johnson RD et al. Cardiovascular activity of some substituted 2-aminobenzoquinolizines. J. Med. Chem.15(1), 91–94 (1972).
  • Maryanoff BE , McComseyDF, TaylorRJet al. Synthesis and stereochemistry of 7-phenyl-2-propionanilidobenzo[a]quinolizidine derivatives. Structural probes of fentanyl analgesics. J. Med. Chem. 24(1), 79–88 (1981).
  • Vardanyan R , VijayG, NicholGSet al. Synthesis and investigations of double-pharmacophore ligands for treatment of chronic and neuropathic pain. Bioorg. Med. Chem. 17(14), 5044–5053 (2009).
  • Tollenaere JP , MoereelsH, RaymaekersLA. Atlas of the Three-Dimensional Structure of Drugs, Vol. 1. Elsevier/North-Holland Inc., Amsterdam, The Netherlands (1979).
  • Koch MHJ , de Ranter CJ, Rolies M, Dideberg O. N-[4-(methoxymethyl)-1-(2-phenylethyl)-4-piperidinyl]-N-phenylpropanamide. Acta Crystallogr. Sect. B32, 2529–2531 (1976).
  • Spickett W . Compounds affecting the central nervous system. II. Substituted 1,2,3,4-tetrahydropyrido [4,3-b] indoles.J. Med. Chem.9(3), 436–438 (1966).
  • Berger JG , DavidsonF, LangfordGE. Synthesis of some conformationally restricted analogs of fentanyl.J. Med. Chem.20(4), 600–602 (1977).
  • Wang Z -X, Zhu Y-C, Jin W-Q et al. Stereoisomers of N-[1-(2-hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]N-phenylpropanamide: synthesis, stereochemistry, analgesic activity, and opioid receptor binding characteristic. J. Med. Chem.38(18), 3652–3659 (1995).
  • Brine GA , StarkPA, LiuJYet al. Enantiomers of diastereomeric cis-N-[1-(2-hydroxy-2-phenylethyl)-3-methyl-4-piperidyl]-N-phenylpropanamides: synthesis, x-ray analysis, and biological activities. J. Med. Chem. 38(9), 1547–1557 (1995).
  • Rice KC , JacobsonAE, BurkeTR Jr et al. Irreversible ligands with high selectivity toward δ or µ opiate receptors. Science220(4594), 314–316 (1983).
  • Burke TR Jr, Bajwa BS, Jacobson AE et al. Probes for narcotic receptor mediated phenomena. 7. Synthesis and pharmacological properties of irreversible ligands specific for µ or δ opiate receptors. J. Med. Chem.27(12), 1570–1574 (1984).
  • Burke TR Jr, Jacobson AE, Rice KC et al. Probes for narcotic receptor mediated phenomena. 12. cis>-(+)-3-methyl-fentanyl isothiocyanate, a potent site-directed acylating agent for δ opioid receptors. Synthesis, absolute configuration, and receptor enantioselectivity. J. Med. Chem.29(6), 1087–1093 (1986).
  • Chen B -Y, Jin W-Q, Chen Jie et al. Analgesic activity and selectivity of isothiocyanate derivatives of fentanyl analogs for opioid receptor. Life Sci.65(15), 1589–1595 (1999).
  • Dardonville C , Fernandez-FernandezG, Gibbons S-L et al. Synthesis and pharmacological studies of new hybrid derivatives of fentanyl active at the µ-opioid receptor and I2–imidazoline binding sites. Bioorg. Med. Chem.14(19), 6570–6580 (2006).
  • Weltrowska G , ChungNN, LemieuxCet al. “Carba”-analogs of fentanyl are opioid receptor agonists. J. Med. Chem. 53(7), 2875–2881 (2010).
  • Srulevitch DB , LienEJ. 4-phenylamidopiperidines: synthesis, pharmacological testing and SAR analysis.Acta Pharm. Jugoslavica41(2), 89–106 (1991).
  • Gupta PK , YadavSK, BhutiaYDet al. Synthesis and comparative bioefficacy of N-(1-phenethyl-4-piperidinyl)propionanilide (fentanyl) and its 1-substituted analogs in Swiss albino mice. Med. Chem. Res. 22(8), 3888–3896 (2013).
  • Vartanyan RS , Gyul‘budagyanAL, KhanamiryanA Kh et al. Synthesis of 1-phenethyl-2-methyl- and 1-methyl-2-phenethyl-4-(N-propionylanilino)hexahydro pyridazines. Arm. Khim. Zh.40(9), 563–569 (1987).
  • Jilek J , RajsnerM, ValentaVet al. Synthesis of piperidine derivatives as potential analgesic agents. Coll. Czech. Chem. Comm. 55(7), 1828–1853 (1990).
  • Morphy R , RankovicZ. Designed multiple ligands, an emerging drug discovery paradigm.J. Med. Chem.48(21), 6523–6543 (2005).
  • Dietis N , GuerriniR, SalvadoriCGet al. Simultaneous targeting of multiple opioid receptors: a strategy to improve side-effect profile. Br. J. Anaesth. 103(1), 38–49 (2009).
  • Liu Z , ZhangJ, ZhangA. Design of multivalent ligand targeting G-protein-coupled receptors.Curr. Pharm. Des.15(6), 682–718 (2009).
  • Schiller PW . Bi- or multifunctional opioid peptide drugs.Life Sci.86, 598–603 (2010).
  • Shonberg J , ScammellsPJ, CapuanoB. design strategies for bivalent ligands targeting GPCRs.ChemMedChem6, 963–974 (2011).
  • Balboni G , SalvadoriS, MarczakEDet al. Opioid biunctional ligands from morphine and the opioid pharmacophore Dmt-Tic. Eur. J. Med. Chem. 46(2), 799–803 (2011).
  • Hruby VJ , PorrecaF, YamamuraHIet al. New paradigms and tools in drug design for pain and addiction. AAPS J. 8(3), E450–E460 (2006).
  • Kumirov R , VK, Nichol GS et al. Synthesis and biological evaluation of new opioid agonist and neurokinin-1 antagonist bivalent ligands. Bioorg. Med. Chem.19(20), 6135–6142 (2011).
  • Petrov RR , VardanyanRS, LeeYSet al. Synthesis and evaluation of 3-aminopropionyl substituted fentanyl analogs for opioid activity. Bioorg. Med. Chem. Lett. 16(18), 4946–4950 (2006).
  • Nichol GS , VardanyanR, HrubyVJ. Synthesis and crystallographic study of N´-(1-benzylpiperidin-4-yl)acetohydrazide.J. Chem. Crystallography40(11), 961–964 (2010).
  • Vardanyan R , KumirovVK, HrubyVJ. Improved synthesis of d,l-fluoro-citric acid.J. Fluorine Chem.132(11), 920–924 (2011).
  • Porreca F , TakemoriAE, SultanaMet al. Modulation of mu-mediated antinociception in the mouse involves opioid delta-2 receptors. J. Pharm. Exp. Therapeut. 263(1), 147–152 (1992).
  • Heyman JS , VaughtJL, MosbergHIet al. Modulation of mu-mediated antinociception by delta agonists in the mouse: selective potentiation of morphine and normorphine by [D-Pen2,D-Pen5]enkephalin. Eur. J. Pharm. 165(1), 1–10 (1989).
  • Heyman JS , JangQ, RothmanRBet al. Modulation of µ-mediated antinociception by delta agonists: characterization with antagonists. Eur. J. Pharm. 169(1), 43–52 (1989).
  • Schiller PW , FundytusME, MerovitzLet al. The opioid µ agonist/δ antagonist DIPP-NH2[ψ] produces a potent analgesic effect, no physical dependence, and less tolerance than morphine in rats. J. Med. Chem. 42(18), 3520–3526 (1999).
  • Rozenfeld R , DeviLA. Receptor heterodimerization leads to a switch in signaling: β-arrestin2-mediated ERK activation by µ-δ opioid receptor heterodimers.FASEB J.21(10), 2455–2465 (2007).
  • Gomes I , GuptaA, FilipovskaJet al. A role for heterodimerization of µ and δ opiate receptors in enhancing morphine analgesia. Proc. Natl Acad. Sci. USA 101(14), 5135–39 (2004).
  • Scherrer G , ImamachiN, Cao Y-Q et al. Dissociation of the opioid receptor mechanisms that control mechanical and heat pain. Cell137(6), 1148–59 (2009).
  • Horan PJ , MattiaA, BilskyEJet al. Antinociceptive profile of biphalin, a dimeric enkephalin analog. J. Pharm. Exp. Ther. 265(3), 1446–1454 (1993).
  • Lee YS , NybergJ, MoyeSet al. Understanding the structural requirements of 4-anilidopiperidine analogs for biological activities at µ and δ opioid receptors. Bioorg. Med. Chem. Lett. 17(8), 2161–2165 (2007).
  • Lee YS , PetrovR, KulkarniVet al. Development of µ/δ opioid ligands: enkephalin analogs containing 4-anilidopiperidine moiety. Adv. Exp. Med. Biol. 611, 517–518 (2009).
  • Lee YS , PetrovR, ParkCKet al. Development of novel enkephalin analogs that have enhanced opioid activities at both µ and δ opioid receptors. J. Med. Chem. 50(22), 5528–5532 (2007).
  • Lee YS , KulkaraniV, CowellSMet al. Development of potent µ and δ opioid agonists with high lipophilicity. J. Med. Chem. 54(1), 382–386 (2011).
  • Xu X , KimCH, ZhuYCet al. (+)-cis-3-methylfentanyl and its analogs bind pseudoirreversibly to the mu opioid binding site: evidence for pseudoallosteric modulation. Neuropharmacology 30(5), 455–62 (1991).
  • Jin WQ , XuH, ZhuYCet al. Studies on synthesis and relationship between analgesic activity and receptor affinity for 3-methyl fentanyl derivatives. Sci. Sin. 24, 710–720 (1981).
  • Maguire P , TsaiN, KamalJet al. Pharmacological profiles of fentanyl analogs at µ, δ and κ opiate receptors. Eur. J. Pharmacol. 213(2), 219–225 (1992).
  • Tollenaere JP , MoereelsH, van Loon M. On conformation analysis, molecular graphics, fentanyl and its derivatives. Prog. Drug Res.30, 91–126 (1986).
  • Martins J , AndrewsP. Conformation-activity relationships of opiate analgesics.J. Comput. Aided Mol. Des.1, 53–72 (1987).
  • Cometta-Morini C , LoewGH. Development of a conformational search strategy for flexible ligands: a study of the potent m-selective opioid analgesic fentanyl.J. Comput. Aided Mol. Des.5, 335–356 (1991).
  • Cometta-Morini C , MaguirePA, LoewGH. Molecular determinants of í receptor recognition for the fentanyl class of compounds.Mol. Pharmacol.41, 185–196 (1992).
  • Brandt W , BarthA, Holtje H-D. A new consistent model explaining structure (conformation)-activity relationships of opiates with í-selectivity. Drug Des. Discov.10, 257–283 (1993).
  • Rong S -B, Zhu Y-C, Jiang H-L et al. Interaction models of 3-methylfentanyl derivatives with mu opioid receptors. Acta Pharmacol. Sin.18, 128–132 (1997).
  • Subramanian GM , PaterliniG, PortoghesePSet al. Molecular docking reveals a novel binding site model for fentanyl at the µ-opioid receptor. J. Med. Chem. 43(3), 381–391 (2000).
  • Dosen-Micovic L , IvanovicM, MicovicV. Steric interactions and the activity of fentanyl analogs at the µ-opioid receptor.Bioorg. Med. Chem.14(9), 2887–2895 (2006).

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.