New morpholine analogues of phencyclidine: Chemical synthesis and pain perception in rats
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)
- et al.
NMDA receptor antagonists as analgesics: focus on the NR2B subtype
Trends Pharmacol Sci
(2001) - et al.
The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats
Pain
(1977) - et al.
Antinociceptive effect of the combination of pentazocine with morphine in the tail-immersion and scald-pain tests in rats
Jpn J Pharmacol
(2000) - et al.
Ketamine and phencyclidine cause a voltage-dependent block of responses to L aspartic acid
Neurosci Lett
(1985) - et al.
The formalin test in mice: dissociation between inflammatory and non-inflammatory pain
Pain
(1987) The NMDA receptor: central role in pain inhibition in rat periaqueductal gray
Eur J Pharmacol
(1988)- et al.
Phencyclidine-induced discriminative stimulus is mediated via phencyclidine binding sites on the N-methyl-D-aspartate receptor-ion channel complex, not via sigma receptors
Behav Brain Res
(2001) - et al.
Syntheses of fluorinated phencyclidine analogs
J Fluorine Chem
(2002) - et al.
Tail immersion test for the evaluation of a nociceptive reaction in mice. Methodological considerations
J Pharmacol Methods
(1989) - et al.
Modified formalin test: characteristic biphasic pain response
Pain
(1989)