New Amine and Aromatic Substituted Analogues of Phencyclidine: Synthesis and Determination of Acute and Chronic Pain Activities

Author(s): Maryam Shokrollahi, Marjaneh Samadizadeh, Mohsen Khalili, Seyed A. Sobhanian, Abbas Ahmadi*

Journal Name: Combinatorial Chemistry & High Throughput Screening
Accelerated Technologies for Biotechnology, Bioassays, Medicinal Chemistry and Natural Products Research

Volume 22 , Issue 8 , 2019

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Background: Phencyclidine (PCP, I) is a synthetic drug with remarkable physiological properties. PCP and its analogues exert many pharmacological activities and interact with some neurotransmitter systems in the central nervous system like particular affinity for PCP sites in NMDA receptors or dopamine uptake blocking or even both.

Aim and Objective: The following research, methyl group with electron-donating and dipole moment characters was added in different positions of phenyl ring along with the substitution of benzylamine (with many pharmacological effects) instead of piperidine ring of I to produce new compounds (II-V) of this family with more analgesic activities.

Materials and Methods: Analgesic activities of these new compounds were measured by tail immersion and formalin tests for acute and chronic pains, respectively. Also, the outcomes were compared with control and PCP (10 mg/kg) groups.

Results: The results indicate that compounds III, IV, and V have more acute and chronic antinociceptive effects than PCP and compound II which may be concerned with more antagonizing activities of these new painkillers for the blockage of dopamine reuptake as well as high affinity for NMDA receptors PCP binding site.

Conclusion: It can be concluded that the benzylamine derivative of phencyclidine with a methyl group on the benzyl position on phenyl ring (V) is a more appropriate candidate to reduce acute and chronic (thermal and chemical) pains compared to other substituted phenyl analogs (II-IV) and PCP.

Keywords: Benzylamine derivatives of phencyclidine, dopamine uptake blocking, NMDA receptors, Tail Immersion tests, formalin tests, synthetic drug.

Ahmadi, A.; Mahmoudi, A. Synthesis with improved yield and study on the analgesic effect of 2-methoxyphencyclidine. Arzneimittelforschung, 2006, 56(5), 346-350. [PMID: 16821645].
al-Deeb, O.A.A. Synthesis and analgesic activity of new phencyclidine derivatives. Arzneimittelforschung, 1994, 44(10), 1141-1144. [PMID: 7818589].
Pechnick, R.N.; Bresee, C.J.; Poland, R.E. The role of antagonism of NMDA receptor-mediated neurotransmission and inhibition of the dopamine reuptake in the neuroendocrine effects of phencyclidine. Life Sci., 2006, 78(17), 2006-2011. []. [PMID: 16288927].
Albuquerque, E.X.; Aguayo, L.G.; Warnick, J.E.; Ickowicz, R.K.; Blaustein, M.P. Interactions of phencyclidine with ion channels of nerve and muscle: Behavioral implications. Fed. Proc., 1983, 42(9), 2584-2589. [PMID: 6303862].
Sircar, R.; Zukin, S. Further evidence of phencyclidine/sigma opioid receptor commonality. In: Phencyclidine: An Update, NIDA Research Monograph 64; Clouet, D.H., Ed.; National Institute on Drug Abuse: Rockville, MD, 1986; p. 14.
Diaz, J. How Drugs Influence Behavior: A Neurobehavioral Approach; Prentice Hall: Englewood Cliffs, 1996.
Ahmadi, A.; Khalili, M.; Hajikhani, R.; Naserbakht, M. New morpholine analogues of phencyclidine: chemical synthesis and pain perception in rats. Pharmacol. Biochem. Behav., 2011, 98(2), 227-233. []. [PMID: 21215770].
Ahmadi, A.; Kermani, M.; Naderi, N.; Hajikhani, R.; Rezaee, N.M.; Javadi, M.; Niknafs, B.N. Synthesis and antinociceptive behaviors of new methyl and hydroxyl derivatives of phencyclidine. Curr. Med. Chem., 2012, 19(5), 763-769. []. [PMID: 22214446].
Ahmadi, A.; Khalili, M.; Marami, S.; Ghadiri, A.; Nahri-Niknafs, B. Synthesis and pain perception of new analogues of phencyclidine in NMRI male mice. Mini Rev. Med. Chem., 2014, 14(1), 64-71. []. [PMID: 24251803].
Ahmadi, A.; Khalili, M.; Fallah, M.; Nahri-Niknafs, B. Synthesis and analgesic properties of new modified analogs of phencyclidine with specific binding on PCP receptor or dopamine inhibition reuptake activities. Pharm. Chem. J., 2015, 49(9), 613-619. [].
Ahmadi, A.; Khalili, M.; Barzin, M.; Pooladi, M.; Bakhtiari, F.; Barjeste, M.; Nahri-Niknafs, B. Synthesis and antinociception properties of phencyclidine derivatives with modified aromatic or cycloalkyl rings and amino group. Monatsh. Chem., 2016, 147(2), 457-464. [].
Ahmadi, A.; Khalili, M.; Mirza, B.; Mohammadi-Diz, M.; Azami-Lorestani, F.; Ghaderi, P.; Nahri-Niknafs, B. Synthesis and antinociception activities of some novel derivatives of phencyclidine with substituted aminobenzothiazoles. Mini Rev. Med. Chem., 2017, 17(1), 78-84. []. [PMID: 27121715].
Ahmadi, A.; Khalili, M.; Abbassi, S.; Javadi, M.; Mahmoudi, A.; Hajikhani, R. Synthesis and study on analgesic effects of 1-[1-[4-methylphenyl][cyclohexyl]-4-piperidinol and 1-[1-[4-methoxyphenyl][cyclohexyl]]-4-piperidinol as Two new phencyclidine derivatives. Arzneimittelforschung, 2009, 59(4), 202-206. [PMID: 19517897].
Okunrobo, L.O.; Usifoh, C.O. Ring opening of phthalimide derivatives with benzylamine: Formation of carboxamides and their pharmacological evaluation. Indian J. Pharm. Sci., 2007, 69(1), 96-100. [].
Maeda, T.; Takase, M.; Ishibashi, A.; Yamamoto, T.; Sasaki, K.; Arika, T.; Yokoo, M.; Amemiya, K. Synthesis and antifungal activity of butenafine hydrochloride (KP-363), a new benzylamine antifungal agent. Yakugaku Zasshi, 1991, 111(2), 126-137. []. [PMID: 2056447].
Lommen, G.; De Bruyn, M.; Schroven, M.; Verschueren, W.; Janssens, W.; Verrelst, J.; Leysen, J. The discovery of a series of new non-indole 5HT1D agonists. Bioorg. Med. Chem. Lett., 1995, 5(22), 2649-2654. [].
Choi, D.; Stables, J.P.; Kohn, H. Synthesis and anticonvulsant activities of N-Benzyl-2-acetamidopropionamide derivatives. J. Med. Chem., 1996, 39(9), 1907-1916. []. [PMID: 8627614].
Morieux, P.; Stables, J.P.; Kohn, H. Synthesis and anticonvulsant activities of N-benzyl (2R)-2-acetamido-3-oxysubstituted propionamide derivatives. Bioorg. Med. Chem., 2008, 16(19), 8968-8975. []. [PMID: 18789868].
Peterson, U. Quinolone Antibiotics: The Development of Moxifloxacin. In: IUPAC, Analogue-based Drug Discovery; Fischer, J.; Ganellin, C.R., Eds.; John Wiley & Sons, 2006; pp. 338-342.
Van Lommen, G.R.E.; De Bruyn, M.F.L.; Schroven, M.F.J. Derivatives of 2,2'-iminobisethanol. US patent 4654362. 1987.
Dubuisson, D.; Dennis, S.G. The formalin test: A quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain, 1977, 4(2), 161-174. []. [PMID: 564014].
Ramabadran, K.; Bansinath, M.; Turndorf, H.; Puig, M.M. Tail immersion test for the evaluation of a nociceptive reaction in mice. Methodological considerations. J. Pharmacol. Methods, 1989, 21(1), 21-31. []. [PMID: 2704245].
Maddox, V.H.; Godefroi, E.F.; Parcell, R.F. The synthesis of phencyclidine and other larylcyclohexylamines. J. Med. Chem., 1965, 8, 230-235. []. [PMID: 14332667].
Ahmadi, A.; Solati, J.; Hajikhani, R.; Onagh, M.; Javadi, M. Synthesis and analgesic effects of 1-[1-(2-methylphenyl)(cyclohexyl)]-3-piperidinol as a new derivative of phencyclidine in mice. Arzneimittelforschung, 2010, 60(8), 492-496. [PMID: 20863005].
Bruylants, p. This study deals with the reaction of organo-magnesium compounds on nitriles. Bull. Soc. Chim. Belg., 1926, 35, 139-154.
Kalir, A.; Edery, H.; Pelah, Z.; Balderman, D.; Porath, G. 1-Phenycycloalkylamine derivatives. II. Synthesis and pharmacological activity. J. Med. Chem., 1969, 12(3), 473-477. []. [PMID: 4977945].
March, J. Advanced Organic Chemistry, Reactions. Mechanisms, and Structure, 2nd ed; McGraw-Hill: St. Louis, MO, 1977, p. 816.
Carey, F.A.; Sundberg, R.J. Advanced Organic Chemistry, Part B: Reactions and Synthesis; Plenum Press: New York, 1977, pp. 172-175.
Yoshimura, J.; Ohgo, Y.; Sato, T. Steric difference between the substitution reaction products of lithium alkyls and grignard reagents with α-aminonitriles. An asymmetric reproduction. J. Org. Chem., 1964, 86, 3858-3862.
Ferle-Vidović, A.; Kaštelan, M.; Petrović, D.; Šuman, L.; Kaselj, M.; Škare, D.; Mlinarić-Majerski, K. Synthesis and biological activity of phencyclidine and its adamantylamine derivatives. Eur. J. Med. Chem., 1993, 28(3), 243-250. [].
Carlson, K.M.; Wagner, G.C. Effects of phencyclidine on schedule-controlled responding following neurotoxic lesions of the striatum. Life Sci., 2005, 77(4), 372-385. []. [PMID: 15894007].
Johnson, K.M.; Jones, S.M. Neuropharmacology of phencyclidine: Basic mechanisms and therapeutic potential. Annu. Rev. Pharmacol. Toxicol., 1990, 30, 707-750. []. [PMID: 2160793].

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Article Details

Year: 2019
Published on: 16 October, 2019
Page: [570 - 576]
Pages: 7
DOI: 10.2174/1386207322666191016152157
Price: $65

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