New morpholine analogues of phencyclidine: Chemical synthesis and pain perception in rats

https://doi.org/10.1016/j.pbb.2010.12.019Get rights and content

Abstract

Phencyclidine (PCP, I) and most its derivatives have demonstrated some pharmacological effects. Accordingly, in this study, the new methoxy (III) and hydroxy-methyl (IV) morpholine PCP derivatives were synthesized. The acute and chronic pain activities of these drugs (III, IV) were investigated by tail immersion and formalin tests on rats and the results were compared with those in PCP, PCM (PCP-morpholine, II), and methyl-PCM (V). Findings indicated that III (6 mg/kg, i.p.) generates more analgesic effects in tail immersion test in comparison with I and II in 20, 40, 45 and 55 min post-injection. These effects were observed in 10, 20, 40, 45 and 50 min after the application of IV (at the same dosage). This analgesic effect was markedly seen in 20, 40, 45 and 50 min after compound IV's application in comparison with the drugs (I–V). In formalin test analysis, the acute chemical pain (Phase I) could not be affected by any drugs (I–V) while chronic formalin pain would be diminished by these new synthesized drugs (III and IV), especially in late Phase II, compared to I and II at the dosage of 6 mg/kg. It is, therefore, concluded that these new synthesized PCP derivates including methoxy-PCM (III) and hydroxy-methyl-PCM (IV) could substantially and respectively diminish acute thermal and chronic chemical pains.

Research Highlights

► New analgesic morpholine derivatives of phencyclidine.

Introduction

1-(1-phenylcyclohexyl) piperidine (Phencyclidine, CAS 77-10-1, PCP, I) is a synthetic drug with outstanding physiological properties. It is initially synthesized in the early 1950 s as a potential surgical anesthetic. PCP allows patients to enter into a trance-like state in which the ‘perception’ of pain could be separated from the ‘sensation’ of pain, a state that has been termed ‘dissociative anesthesia’ (Erard et al., 1980). It is also a non-competitive N-methyl-d-asparate (NMDA) receptor antagonist, which has been demonstrated to produce psychotomimetic effects on humans, but it is a widely abused drug (Mori et al., 2001). Phencyclidine and its derivatives influence the central nervous system and display analgesic, stimulant, depressant, and hallucinogenic effects due to the existence of specific binding sites in the brain (Al-deeb, 1994, Ahmadi and Mahmoudi, 2006).

PCP binds into the N-methyl-d-asparate (NMDA) receptor complex and blocks NMDA-mediated gating of the calcium channel conductance (Kapur and Seeman, 2002, Olney et al., 1991). They are classified with many behavioral effects in common with other phencyclidine-like drugs including anaesthetics, antinociceptives, psychotomimetics, anticonvulsants, neuroprotectives and amnesic drugs concern to non-competitive, ‘open channel blockers’ of the NMDA receptor (Honey et al., 1985). However, different receptors in the central nervous system are involved in the modulation of behavioral effect of PCP and its analogues.

Many PCP derivatives (with changes in substitution on the molecule) have been synthesized and their pharmacological activities have been tested in recent years (Al-deeb, 1996, Ogunbadeniyi and Adejare, 2002, Ahmadi and Mahmoudi, 2005). 1-[1-[2-methoxyphenyl] [cyclohexyl] morpholine (methoxy-PCM, III) and 1-[1-[4-hydroxy-2-methylphenyl] [cyclohexyl] morpholine, (hydroxy-methyl-PCM, IV) as new analogues of I, have been synthesized in this study. Methoxy and hydroxyl-methyl groups were added to the aromatic ring and morpholine group instead of the piperidine ring of the molecule to examine analgesic effects on rats using the tail immersion (as a model of acute thermal pain) and the formalin (as a model of acute chemical and chronic pain) tests. The results were compared with PCP and PCM (1-[1-phenylcyclohexyl] morpholine, CAS 2201-40-3, PCP-morpholine, II) and methyl-PCM (1-[1-[4-methylphenyl][cyclohexyl] morpholine, V) (Ahmadi et al., 2010; Ahmadi et al., 2011).

As it was revealed in previous works (Ahmadi et al., 2009, Ahmadi et al., 2010) with this family of compounds, the incorporation of methyl and methoxy groups to the aromatic ring of the molecule would generate pronounced effects on electron distribution and dipole moments because of their high electron donating characters (Johnson et al., 1981). The same have been applied to the incorporation of morpholine, with many pharmacological behaviors (Beckett and Kourounakis, 1976, Chen et al., 2003), and analgesic properties (Beckett and Kourounakis, 1976). In addition, the hydroxyl group with high hydrophilic, polarity, and solubility properties (Shebley et al., 2006) may produce more analgesic effects in this family. Also, to increase the low potency (Soine, 1986, Budd, 1981) of PCM, compared to PCP, these changes are applied to the PCM molecule in anticipation of producing the pronounced effects on the activity of the new synthesized drugs (III and IV) in the current study.

Section snippets

General

Cyclohexanone, piperidine, bromo benzene, magnesium turning, diethyl ether, 4-bromo toluene, morpholine, 2-bromo anisole, 4-chloro-3-methyl phenol and all other chemicals were purchased from Merck Chemical Co. (Darmstadt, Germany). Later, the melting points (uncorrected) were determined using a digital Electrothermal melting point apparatus (model 9100, Electrothermal Engineering Ltd., Essex, UK). 1H and 13C NMR spectra were recorded on Bruker 300 MHz (model AMX, Karlsruhe, Germany) spectrometer

Chemistry

Phencyclidine, 1-[1-phenylcyclohexyl] morpholine, 1-[1-[2-methoxylphenyl] [cyclohexyl] morpholine, 1-[1-[4-hydroxy-2-methylphenyl][cyclohexyl] morpholine, and 1-[1-[4-methylphenyl] [cyclohexyl] morpholine (I–V) were synthesized by the reaction of substituted Grignard reagent and carbonitrile compounds. The addition of methyl and methoxy groups to the aromatic ring (having high electron donating, electron distribution, and dipole moments characters) and hydroxyl group (with strong hydrophilic,

Discussion

Phencyclidine is well absorbed by all routes of administration. The intravenous administration results, in a very rapid (in seconds) onset of action with peak effect, were reached after 10 min (Mozayani, 2003).Interestingly; studies on a single bolus of PCP in rats have shown that the peak PCP concentration in the brain occurs in 30 s. This apparent contradiction with the onset of peak effects is probably due to the fact that the serum level decreases 30 times faster than the brain

Conclusion

It is concluded that these new synthesized derivates of PCP including methoxy-PCM (III) and hydroxy-methyl-PCM (IV) could substantially and respectively diminish acute thermal and chronic chemical pains.

Conflict of interest

This research is not a part of our normal lecturing, employment, consultation, and involvement; and no institution will require any rights from this work.

In addition, no patent has been applied nor any commercial right has been given to any company and/or institution, and it will not be done later either.

Acknowledgements

This work was done as a research project at Islamic Azad University, Karaj branch by financial support of INFS (Iranian National Foundation Support) and we are indebted them.

The authors would also like to express their appreciation to Mojdeh Javadi and Fariba Ansari for their assistance in the chemical experiments and pharmacological tests. Our sincere thanks go to Ahmad Jahan Latibari and Navid Rahmani for their attempts in editing this paper, as well as Natasha Qale, the CamTESOL

References (36)

  • M.O. Abdol-Rahman et al.

    Action of Grignard reagents aryllithium on 1, 1-disubstituted cyclohexane derivatives

    Egypt J Chem

    (1975)
  • A. Ahmadi et al.

    Synthesis and biological properties of 2- hydroxy-1- (1- phenyltetralin) piperidine and some of its intermediates as derivatives of phencyclidine

    Arzneimittelforschung

    (2005)
  • A. Ahmadi et al.

    Synthesis with improved yield and study on analgesic effect of 2-methoxyphencyclidine

    Arzneimittelforschung

    (2006)
  • A. Ahmadi et al.

    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)
  • A. Ahmadi et al.

    Synthesis and determination of acute and chronic pain activities of 1-[1-[3-methyphenyl][tetralyl]] piperidine as a new derivative of phencyclidine via tail immersion and formalin tests

    Arzneimittelforschung

    (2010)
  • A. Ahmadi et al.

    Synthesis and determination of acute and chronic pain activities of 1-[1-[4-methylphenyl][cyclohexyl] morpholine as a new phencyclidine derivative in Rats

    Arzneimittelforschung

    (2011)
  • O.A.A. Al-deeb

    Synthesis and analgesic activity of new phencyclidine derivatives

    Arzneimittelforschung

    (1994)
  • O.A.A. Al-deeb

    New analgesic derived from the phencyclidine analogue hiencyclidine

    Arzneimittelforschung

    (1996)
  • Cited by (0)

    View full text