Design, synthesis, and evaluation of dihydropyrimidinone (DHPM) based muscarinic receptor antagonist

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• 作者：Badri N. Acharya (1)
  G. B. Dharma Rao (1)
  Deo Kumar (1)
  Pravin Kumar (1)
  Mahabir P. Kaushik (1)
  
  1. Defence R&D Establishment ; Jhansi Road ; Gwalior ; 474002 ; MP ; India
  
• 关键词：Antimuscarinic ; Atropine ; Pharmacophore ; Biginelli reaction ; DHPM
• 刊名：Medicinal Chemistry Research
• 出版年：2015
• 出版时间：April 2015
• 年：2015
• 卷：24
• 期：4
• 页码：1763-1775
• 全文大小：2,922 KB
• 参考文献：1. Abrams, P, Andersson, KE (2007) Muscarinic receptor antagonists for overactive bladder. BJU Int 100: pp. 987-1006 CrossRef
  2. Accelrys, Inc. Discovery Studio (2007) version 2.0: San Diego, CA
  3. Amenta, F, Tayebati, S (2008) Pathways of acetylcholine synthesis, transport and release as targets for treatment of adult-onset cognitive dysfunction. Curr Med Chem 15: pp. 488-498 CrossRef
  4. Araujo, DM, Lapchak, PA, Quirion, R (1991) Heterogeneous binding of [3H]4-DAMP to muscarinic cholinergic sites in the rat brain: Evidence from membrane binding and autoradiographic studies. Synapse 9: pp. 165-176 CrossRef
  5. Ayala, LE, Ahmed, T (1989) Is there loss of protective muscarinic receptor mechanism in asthma?. Chest 96: pp. 1285-1291 CrossRef
  6. Bajgar, J (2004) Organophosphate/nerve agent poisoning: mechanism of action, diagnosis, prophylaxis and treatment. Adv Clin Chem 38: pp. 151-216 CrossRef
  7. Barnes, PJ (2000) The Pharmacological Properties of Tiotropium Chest 117: pp. 63S-66S
  8. Beesley, WN (1994) Sheep dipping, with special reference to the UK. Pestic Outlook 5: pp. 16-21
  9. Ben-Barak, J, Gazit, H, Silman, I, Dudai, Y (1981) In vivo modulation of the number of muscarinic receptors in rat brain by cholinergic ligands. Eur J Pharmacol 74: pp. 73-81 CrossRef
  10. Bhattacharjee, AK, Pomponio, JW, Evans, SA, Pervitsky, D, Gordon, RK (2013) Discovery of subtype selective muscarinic receptor antagonists as alternatives to atropine using in silico pharmacophore modeling and virtual screening methods. Bioorg Med Chem 21: pp. 2651-2662 CrossRef
  11. Bonner, T, Buckley, N, Young, A, Brann, M (1987) Identification of a family of muscarinic receptor genes. Science 237: pp. 527-532 CrossRef
  12. Chess-Williams, R, Chapple, CR, Yamanishi, T, Yasuda, K, Sellers, DJ (2001) The minor population of M3-receptors mediates contraction of human detrusor muscle in vitro. J Auton Pharmacol 21: pp. 243-248 CrossRef
  13. Choo, LK, Mitchelson, F (1988) J Pharm Pharmacol 40: pp. 288-289 CrossRef
  14. Den, HA, den, AJ (1987) Modification of alpha 1-receptor-operated channels by mebeverine in smooth muscle cells of guinea-pig taenia caeci. Eur J Pharmacol 138: pp. 367-374 CrossRef
  15. Dewey, SL, Macgregor, RR, Brodie, JD, Bendriem, B, King, PT, Volkow, ND, Schlyer, DJ, Fowler, JS, Wolf, AP, Gatley, SJ, Hitzemann, R (2004) Mapping muscarinic receptors in human and baboon brain using [N-11C-methyl]-benztropine. Synapse 5: pp. 213-223 CrossRef
  16. Doods, HN, Willim, KD, Boddeke, HWGM, Entzeroth, M (1993) Characterization of muscarinic receptors in guinea-pig uterus. Eur J Pharmacol 250: pp. 223-230 CrossRef
  17. Giachetti, A, Giraldo, E, Ladinsky, H, Montagna, E (1986) Binding and functional profiles of the selective M1 muscarinic receptor antagonists trihexyphenidyl and dicyclomine. Br J Pharmacol 89: pp. 83-90 CrossRef
  18. Gilman, A (1984) G proteins and dual control of adenylate cyclase. Cell 36: pp. 577-579 CrossRef
  19. Giraldo, E, Michelletti, R, Montagna, E, Giachetti, A, Vigano, M, Ladinsky, H, Melchiorre, C (1988) Binding and functional characterization of the cardioselective muscarinic antagonist methoctramine. J Phramacol Exp Ther 244: pp. 1016-1020
  20. Greene, J, Kahn, S, Savoj, H, Sprague, P, Teig, S (1994) Chemical function queries for 3D database search. J Chem Inf Comput Sci 34: pp. 1297-1308 CrossRef
  21. Guner, OF (2000) Pharmacophore perception, development and use in drug design. International University Line, La Jolla
  22. Haab, F, Stewart, L, Dwyer, P (2004) Darifenacin, an M3 selective receptor antagonist, is an effective and well-tolerated once-daily treatment for overactive bladder. Eur Urol 45: pp. 420-429 CrossRef
  23. Hammer, R, Berrie, CP, Birdsall, NJM, Burgen, ASV, Hulme, EC (1980) Pirenzepine distinguishes between different subclasses of muscarinic receptors. Nature 283: pp. 90-92 CrossRef
  24. Jain, N, Kumar, P, Kumar, D, Mavai, Y, Vijayaraghavan, R (2012) Development and evaluation of combined drug formulation for Autojec-injector, for emergency application in organophosphate poisoning. Def Sci J 62: pp. 105-111 CrossRef
  25. Jones, LWJ, Modes, DT (1991) Possible allergic reactions to cyclopentolate hydrochloride: case reports with literature review of uses and adverse reactions. Opthalmic Physiol Optics 11: pp. 16-21 CrossRef
  26. Kubo, N, Shirakawa, O, Kuno, T, Tanaka, C (1987) Antimuscarinic effects of antihistamines: quantitative evaluation by receptor-binding assay. Jpn J Pharmacol 43: pp. 277-282 CrossRef
  27. Kumar, P, Kumar, D, Vijayaraghavan, R, DasGupta, S (1997) Effect of 1-chloroacetophenone (CN) and dibenz (b,f)-1,4 oxazepine (CR) vapour on some cardiovascular and respiratory variables in anaesthetized rats. Ind J Pharmacol 29: pp. 238-243
  28. Lang, WJ, Rush, ML (1973) Cardiovascular responses to injections of cholinomimetic drugs into central ventricles of unanaesthtized dogs. Br J Pharmacol 47: pp. 196-205 CrossRef
  29. MacLaughlin, B, Rickels, K, Abidi, M, Toro, R (1969) Meprobamate-benactizine (deprol) and placebo in depressed outpatient populations. Psychosomatics 10: pp. 73-81 CrossRef
  30. Maggio, R, Barbier, P, Bolognesi, ML, Minarini, A, Tedeschi, D, Melchiorre, C (1994) Binding profile of selective muscarinic receptor antagonist tripitramine. Eur J Pharmacol Mol Pharmacol 268: pp. 459-462 CrossRef
  31. Malbon, C (2005) G proteins in development. Nature Review Molecular and Cell Biology 6: pp. 689-701 CrossRef
  32. Marrs, TC (1993) Organophosphate poisoning. Pharmacol Ther 58: pp. 51-66 CrossRef
  33. Munro, NB, Watson, AP, Ambrose, KR, Griffin, GD (1990) Treating exposure to chemical warfare agents: implications for health care providers and community emergency planning. Environ Health Perspect 89: pp. 205-215 CrossRef
  34. Nagao, M, Takatori, T, Matsuda, Y, Nakajima, M, Iwase, H, Iwadate, K (1997) Definitive evidence for the acute sarin poisoning diagnosis in the Tokyo subway. Toxicol Appl Pharmacol 144: pp. 198-203 CrossRef
  35. Nilvebrant, L, Hallen, B, Larsson, G (1997) Tolterodine- a new bladder- selective muscarinic receptor antagonist: preclinical pharmacological and clinical data. Life Sci 60: pp. 1129-1136 CrossRef
  36. Noronha-Blob, L, Kachur, JF (1991) Enantiomers of oxybutynin: in vitro pharmacological characterization at M1, M2 and M3 muscarinic receptors and in vivo effects on urinary bladder contraction, mydriasis and salivary secretion in guinea pigs. J Pharmacol Exp Ther 256: pp. 562-567
  37. Oki, T, Sato, S, Miyata, K, Yamada, S (2005) Muscarinic receptor binding, plasma concentration and inhibition of salivation after oral administration of a novel antimuscarinic agent, solifenacin succinate in mice. Br J Pharmacol 145: pp. 219-227 CrossRef
  38. Olianas, MC, Onali, P (1999) PD102807, a novel muscarinic M4 receptor antagonist, discriminates between striatal and cortical muscarinic receptors coupled to cyclic AMP. Life Sci 65: pp. 2233-2240 CrossRef
  39. Peretto, I, Forlani, R, Fossati, C, Giardina, GAM, Giardina, GAM, Porta, E, Petrillo, P, Radaelli, C, Radice, L, Raveglia, LF, Santoro, E, Scudellaro, R, Scarpitta, F, Bigogno, C, Misiano, P, Dondio, GM, Rizzi, A, Armani, E, Amari, G, Civelli, M, Viletti, P, Bergamaschi, M, Delcanale, M, Salcedo, C, Fernandez, AG, Imbimbo, BP (2007) Discovery of diaryl imidazolidin-2-one derivatives, a novel class of muscarinic M3 selective antagonists (Part 1). J Med Chem 50: pp. 1571-1583 CrossRef
  40. Rao, GBD, Acharya, BN, Kaushik, MP (2013) An efficient synthesis of 尾-ketoesters via transesterification and its application in Biginelli reaction under solvent-free, catalyst-free conditions. Tetrahedron Letter 54: pp. 6644-6647 CrossRef
  41. Smith, MC, Riskin, BJ (1991) The clinical use of barbiturate in neurological disorders. Drugs 42: pp. 365-378 CrossRef
  42. Szinicz, L (2005) History of chemical and biological warfare agents. Toxicology 214: pp. 167-181 CrossRef
  43. Thiermann, H, Worek, F, Kehe, K (2013) Limitations and challenges in treatment of acute chemical warfare agent poisoning. Chem Biol Interact 206: pp. 435-443 CrossRef
  44. Valenstein, ES (2005) The war of the soups and sparks: the discovery of neurotransmitters and the dispute over how nerves communicate. Columbia University Press, New York
  45. Vannucchi, MG, Scali, C, Kopf, SR, Pepeu, G, Casamenti, F (1997) Selective muscarinic antagonists differentially affect in vivo acetylcholine release and memory performances of young and aged rats. Neuroscience 79: pp. 837-846 CrossRef
  46. Wanke, E, Ferroni, A, Malgaroli, A, Ambrosini, A, Pozzan, T, Meldolesi, J (1987) Activation of a muscarinic receptor selectively inhibits a rapidly inactivated Ca2+ current in rat sympathetic neurons. Proc Natl Acad Sci USA 84: pp. 4313-4317 CrossRef
  
• 刊物主题：Pharmacology/Toxicology; Biochemistry, general; Cell Biology;
• 出版者：Springer US
• ISSN：1554-8120

文摘

Organophosphorus compounds (OPCs) are highly toxic being used in pest control. Some of the OPCs are lethal chemical warfare agents and their toxicity is due to inhibition of acetylcholine esterase (AChE), the enzyme that hydrolyses neurotransmitter acetylcholine (ACh). Due to over accumulation of ACh at muscarinic acetylcholine receptors (mAChRs) several cholinergic functions increase uncontrollably like salivation, lacrimation, urination, defecation, gastrointestinal upset, and emesis. Atropine is used to treat OPC poisoning because it is a mAChR antagonist. But atropine has several unwanted side effects including dryness of mucous membrane, hot and dry skin, tachycardia, and restlessness. Our goal was to find out molecules having antimuscarinic activity which may be developed as potential alternatives for atropine in future. In this work pharmacophore-based screening, structure identification, synthesis and ex vivo evaluation of a new class of muscarinic receptor antagonist are described. The antagonists are based on dihydropyrimidinone scaffold with a tertiary or quaternary amine side group. A series of molecules were evaluated for preliminary pharmacological activity on rat ileum out of which three molecules found active.