Synthesis with Improved Yield and Study on the Analgesic Effect of 2-Methoxyphencyclidine

Analgetika Analget ika · Antiphlo Antiphlogistika gistika · Antirheu Antirheumatika matika · Entzündun Entzündungshemm gshemmer er

Synthesis with Improved Yield and Study on the Analgesic Effect of 2-Methoxyphencyclidine Abbas Ahmadi and Ali A li Mahmoudi

Department of Science, School of Chemistry, Islamic Azad University, Karaj (Iran) Corresponding author: Prof. Dr. Abbas Ahmadi, Department of Science, School of Chemistry, Islamic Azad University, P. O. Box 31485-313, Karaj (Iran); e-mail: abbas −ahmady −[email protected]

Summary Phencyclidine (1-(1-phenylcyclohexyl) (1-(1-phenylcyclohexyl)pipiperidine, CAS 956-90-1, PCP) has shown analgesic effects. Some of its derivatives have been synthesized and their biological properties were studied. Since a methoxy metho xy group has been added to the position 2 of the cyclohexane ring of PCP, PCP, the resulting compound is more polar than PCP. This compound was synthesized using an improved method with a higher yield. Its analgesic effect was studied studi ed using the tail-flick test on rats and was compa compared red with that of ketam ketamine ine (CAS 1867-66-9).

The results showed that 2-methoxyphencyclidine increased tail-flick latencies as compared to the control group. The maximum analgesic analgesic effect of the compound occurred 5−10 min after its in jection, while the effect of ketamine was observed 10−25 min after injection.

Zusammenfassung Key words ᭿ ᭿ ᭿

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Analgesics CAS 956-90-1 2-Methoxyphencyclidine, 2-Metho xyphencyclidine, analgesic effect, rat, synthesis Phencyclidine derivatives

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2-Methoxyphencyclidine

Synthese mit verbesserter Ausbeute und Untersuchung der analgetischen Wirkung von 2-Methoxyphencyclidin Phencyclidin (1-(1-Phenylcyclohexyl (1-(1-Phenylcyclohexyl))piperidine, CAS 956-90-1, PCP) besitzt analgetische Wirkung. Einige Derivate von PCP werden synthetisiert und ihre biologischen Eigenschaften untersucht. Da eine Methoxy-Gruppe in Position 2 des Cyclohexan-Rings von PCP eingeführt wurde, besitzt die neue Verbindung gröβere Polarität und Aktivität als PCP. Diese Verbindung wurde nach einer verbesserten Methode mit höherer Ausbeute synthetisiert. Die analgetische Wirkung wurde im Tail-flick-T Tail-flick-Test est an Ratten im Vergleich zu Ketamin (CAS 1867-66-9) untersucht.

Die Ergebnisse zeigten, da β 2-Metho xyphencyclidin die Verzögerung im Ta Taililflick-Test im Vergleich zur Kontrollgruppe erhöhte, wobei die maximale analgetische Wirkung 5 bis 10 min nach der Verabreichung beobachtet wurde, während de r entsprechende Effekt von Ketamin nach 10 bis 25 min auftrat.

Arzneim.-Forsch./Drug Res. 56, No. 5, 346−350 (2006)  ECV · Editio Cantor Verlag, Aulendorf (Germany)

Analgesics · Anti-inflammatories · Antiphlogistics · Antirheumatic Drugs

1. Introduction It is well known that, phencyclidine (1-(1-phenylcyclohexyl) hexy l) piperi piperidine dine,, CAS 956956-90-1 90-1,, PCP PCP), ), its deriv derivative ativess and analogues have biological properties and affect the central nervous system. Changes in the phencyclidine molecule can bring about changes in its properties [1]. It is a highly potent and widely abused psychomimetic drug [2]. It displ displays ays analg analgesic esic,, stimu stimulant, lant, depr depressan essantt and hallucinogenic effects and is known to bind to µrecepto rec eptors, rs, but evidence evidence is avail available able suggesting suggesting that it has its own specific receptor [3]. PCP has been shown to exer exertt its analg analgesic esic effect through opiate rec recepto eptors. rs. However Ho wever,, probably the most powe powerful rful approach in characterizing PCP analgesic effect stems from recent pharmacod mac odyna ynamic mic stu studie diess tha thatt hav have e ide identi ntifie fied d spe specif cific ic binding sites in the brain [4]. PCP also was originally introduced as a general anesthetic agent [5 −7], but it was subsequently withdrawn from use in humans because of severe psychomimetic side effects [8 −13]. The focus of research on PCP has shifted from its use as an anesthet anes thetic ic tow toward ard potential potential appli applicatio cations ns as a neur neuroopharmaceutical [14, 15]. PCP binds to the N-methyl-D-asparate (NMDA) receptor complex and blocks NMDA-mediated gating of the calcium channel conductance [16].The most powerful appr approach oach in char characte acterizin rizing g PCP PCP’’s analg analgesic esic effe effect ct stems from recent pharmacodynamic studies that have identified specific binding sites in the brain. PCP and similar simil ar comp compound oundss are class classified ified as nonnon-comp competit etitive ive “open channel blockers” of the NMDA receptor [17, 18]. PCP PC P and ana analog logues ues hav have e man many y be behav havior ioral al eff effec ects ts in common with other phencyclidin phencyclidine-like e-like drugs, including anaesthe anae sthetic, tic, antin antinocic ocicepti eptive, ve, psyc psychoto hotomime mimetic, tic, anti anti-convulsan conv ulsant, t, neur neuropro oprotect tective ive and amne amnesic sic drugs [19] [19].. PCP is a semi-rigid molecule containing a cyclohexane ring with attached aromatic and piperidine rings (see structure formulas). The analgesic effect of ketamine (2-O-chlorophenyl2-methylaminocyclohexane, CAS 1867-66-9; see structure tur e for formul mula), a), ano anothe therr PC PCP P ana analog logue ue,, was fir first st de de-scribed by Domino and collaborators in 1965. Ketamine in low sub-anaesthetic doses is reliable as an analgesic in acute pain [20]. In low sub-anaesthetic doses, ketamine ami ne act actss mor more e sel select ective ively ly as a non non-co -compe mpetit titive ive blocker of the NMDA receptor. It does so by binding to the PCP recognition site in the NMDA receptor complex [21]. At higher concentration, ketamine interacts with opioid receptors, sigma sites, kappa and delta receptors [22, 23]. Since a methoxy group has been added to position 2 of the cyclohexane ring of PCP (2-OCH 3-PCP -PCP), ), this compound is more polar and active than PCP and has previously been synthesized with low yield [24, 25]. In this paper paper,, we synth synthesize esized d 2-me 2-metho thoxy xy phen phencyc cyclidin lidine e with higher yield than the previous methods and tested its analgesic effect by the tail-flick test, comparing it with ketamine ketamine.. Arzneim.-Forsch./Drug Res. 56, No. 5, 346 −350 (2006)  ECV · Editio Cantor Verlag, Aulendorf (Germany)

C6H5

C6H5

N

N

C6H4Cl

NHCH3 O

OH 1

PCP

2

2-OH-PCP

C6H5

3

Ketamine

N OCH3 4

2-OCH 3-PCP

Structure formulas of PCP, 2-OH-PCP, 2-OH-PCP, ketamine and 2-OCH 3-PCP

2. Material and methods 2.1. General Cyclohexanone, 1,5-dibromopentane, Cyclohexanone, 1,5-dibromopentane, sodium azide, LiAlH4, tetrahydrofuran, sodium hydride, iodomethane and all other chemicals were purchase from Merck (Darmstadt, Germany). Ketamine was purchased from Sigma-Aldrich chemical company (Poole, Dorset, England). Melting points (uncorrected) (uncorrected) were determined using a Gallencam Gallencamp p apparatus (CA (CAT T.No.29 .No.29// 1 MF-370; Watford, Watford, Herts, England) with a capillary tube. H- and 13 C-NMR spectra were recorded on a Bruker 80 MHz, Ac-80 spectrometer spectromet er (Spectros (Spectrospin, pin, Fael Faellanden, landen, Switzerlan Switzerland) d) (internal reference: TMS). IR spectra were recorded on a Shimadzu FTIR 4800 spectrophotometer (Kyoto, Japan). Mass spectra were recorded on a Shimadzu QP-1000 EX spectrometer. Spectroscopic data (IR, 1H- and 13C-NMR) confirmed the structures of all rep reported orted compounds; compounds; the melt melting ing points of know known n com com-pounds could also confirm their identity. The purity of each compound was checked by TLC [dioxin:toluene:ethanol:con[dioxin:toluene:ethanol:concentrate cent rated d ammo ammonia, nia, 50:40:5:5 50:40:5:5 (b (by y volum volumes) es),, as the mobi mobile le phase]. Adult male NMRI rats, weighting about 250−30 300 0 g, wer were e used for pharmacological testing. All procedures were carried out in accordance with institutional guidelines for animal care and use.

2.2. Synthesis of compounds 2.2.1. 1-Phenyl cyclohexanol 5 This compound was prepared in 62 % yield from phenyl magnesium bromide and cyclohexanone according to the known procedure [26]. The product was recrystallized from ether-petroleum benzene (1:1) (m.p. 63 −63.5 °C).

2.2.2. 1-Phenyl cyclohexene 6 This compound was prepared from 1- phenyl cyclohexanol and a mixture of sulfuric and glacial acetic acid according to the known procedure [27] (b.p. 110−111 °C, 5mmHg).

2.2.3. cis-1-Phenylcyclohexane-1, 2-diol (7) This compound was prepar prepared ed from 1-phenylcyc 1-phenylcyclohexen lohexen and KMnO4 at −5 °C according to the known procedure [28]. The product prod uct was rec recrysta rystallize llized d from ethan ethanol-pe ol-petrole troleum um benz benzene ene (1:1) (m.p: 94−96.5 °C).

2.2.4. cis-2-Azido-2-phenylcyclohexanol (8) This compound was prepared from cis-1-phenylcyclohexane1,2-diol and sodium azide and a solution of perchloric acid

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70 % at 5 °C for 5 days [29] and was recrystalized from etherpetroleum benzene (6:1) (m.p. 61 −63 °C).

2.2.5. cis-2-Amino-2-phenylcyclohexanol (9) This com compound pound was pre prepare pared d by ref refluxi luxing ng of ciscis-2-az 2-azidoido-22phenylhexanol phenylhexan ol and LiALH4 in dry ether for 48 h [30] (m.p. 103−104 °C).

2.2.6. cis-2-Piperidino-2-phenylcyclohexanol (2) This compound was prepared from refluxing of cis-2-amino-2phenylhexanol and 1,5-dibromopentane in dry acetone for 2 days [31] (m.p. 135 °C ).

2.2.7. cis-1-Metho cis-1-Methoxy-2-piperidino-2xy-2-piperidino-2phenylcyclohexane (4) A solution containing 150 mg (0.58 mmol) of compound 2 with 127.5 mg (2.34 mmol) of 60 % NaH in 50 ml of dry THF was refluxed for 5 h. The reaction mixture was cooled, then 442 mg (2.32 mmol) ofCH3I was added and the mixture was refluxed again for 5 h. The reaction was quenched by the addition of ice-w ic e-wate aterr. The sol solve vent nt was re remo moved ved and the re resid sidue ue was treated with 5 % solution of HCl. The aqueous layer was separated ra ted and ext extra racte cted d wit with h eth ether er and neu neutr trali alized zed wit with h 10 % NaOH Na OH,, ext extra racte cted d wit with h eth ether er,, dri dried ed ov over er Na2SO4. 147 147.4 .4 mg (93.2 %) of compound 4 was obtained (m.p. 90−92 °C). IR (KB (KBr): r): 305 3050, 0, 297 2979, 9, 292 2925, 5, 160 1600, 0, 1490 1490,, 146 1465, 5, 1371 1371,, 127 1271, 1, -1 1168, 1097, 954.7, 756, 696 cm . 1 H-NMR (CDCl3) (ppm): 1.3−2.3 (18H, m), 3.25 (3H, m), 3.4 − 3.5 (1H, m), 7−7.2 (5H, m). 13 C-NMR (CDCl3) (p.p.m.): 20.3, 21.5, 25.1, 26.2, 31.4, 48.1, 52, 63.4, 84.4, 125.7, 126.7, 128.2, 144.8. MS: m/e (regulatory intensity): 273 (34).

2.3. Pharmacological methods Adult male NMRI rats, bred at the institute of Biochemi Biochemistry stry and Biophysi Bio physics cs at Tehr ehran an Un Univer iversity sity,, were maintained maintained on a 12-h light-dark cycle in a temperature-controlled room (25 ± 1 °C) at 50 % relative humidity. They were allowed free access to a standard laboratory rat chow (Pars Company, Tehran, Iran) and tap water ad libitum. The animals (n = 35, total; 250 −300 g body weight) were randomly assigned to various groups. They were brought into the experimenta experimentall room for acclimatizat acclimatization ion 24 h before the experiment. All experiments were performed between 8 h 0 min and 16 h 0 min under normal room light and at the temperature of 25 °C. All of the animals were in jected by one investigator and evaluated by another one.

tency in s was used as a parameter of pain sensitivity. The light source sour ce was adjus adjusted ted to give an aver average age baseline baseline late latency ncy of about 3−4 s in untreated rats. Two trails of the tail flick test were run at 5-min intervals.

2.3.2. Effect of 2-methoxyphencyclidine and ketamine hydrochloride on analgesic activity 2-Methoxyphencyclidine 2-Methoxyphencycl idine (2-OCH3-PCP -PCP)) was dissolved dissolved in dimethylsulfoxide (DMSO) and was given 15 min before the actuall tes tua testin ting. g. In oth other er gro groups ups,, ani anima mals ls wer were e giv given en sal saline ine (vehicle) and ketamine in saline, respec respectively tively.. The difference in the tail-flick latencies scores were evaluated using analysis of variance (ANOVA). The p< 0.05 0.05 leve levell was cons consider idered ed to rep repres resent ent sign signific ificant ant difference. 2-OCH 3-PCP was injected in two doses (3 and 6 mg/ kg i.p) and the tail-flick latency was determined 2, 5, 10, 15, 20, 25 and 30 min afte afterr inje injectio ction. n. Anoth Another er anal analogue ogue of PCP, ketamine hydrochloride was injected for comparison (at 0.5, 1, 6 mg/kg i.p.).

3. Results 3.1. Chemistry

2-OCH3-PCP was synthesized as outlined in Scheme 1. This compound has been synthesized previously, but in this study, we synthesized it using another method with higher yield. We employed the known procedure for the synthesis of compounds 5 to 8 with the appropriate modifications described previously [26 −29]. 3.2. Pharmacology 3.2.1. The analgesic activity of 2-OCH 3-PCP and ketamine hydrochloride

Intraperitoneal injections of ketamine (0.5, 1, 6 mg/kg) and 2-OCH3-PCP (3 and 6 mg/kg) produced analgesic effects effe cts in the tail-flick test. The experiments experiments sho showed wed thatt two doses tha doses of 2-O 2-OCH CH3-P -PCP CP (3 an and d 6 mg mg/k /kg) g) in in-creas cr eased ed tai tail-f l-flic lick k lat latenc encies ies com compar pared ed to the co contr ntrol ol group receiving DMSO, and the maximum analgesic effect was observed 5 −10 min after its injection (Fig. 1). Ketamine produced analgesia in the tail-flick test in all injected doses (Fig. 2), and the maximum effect was observed 10−15 min after its injection.

2.3.1. Tail-flick test A commer commercially cially available analgesia meter (Apelex, model DS 20, Socrel, Bagneux, France) was used. The test is a modification of the D’Amour and Smith method [4]. Various groups of rats (n = 5 animals/group) were used for the test. The whole body of each rat except the tail was covered with a piece of thick cloth. A beam of light at a temperature of 130 °C was focused onto the last 1−2 cm of the tail. The latency time (in s) at which the animal withdrew its tail was noted before treatment and 2, 5, 10, 15, 20, 25 and 30 min after administration of the drug. A cut-off time of 10 s was used for each light exposure to avoid damage of the tail. The first tail withdrawal la-

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OH O

a

OH

b

C6H5

C6H5

5

C6H5

4

OH C6H5

7

6

d

OCH3 N

C

OH

g

N

NH2

C6H5

C6H5

2

OH

OH

9

N3

e

C6H5

8

Scheme 1: Synthesis of 2-OCH3-PCP. (a) C6H5MgBr, dry ether; (b) H2SO4, ACOH; (c) KMnO4; (d) NaN3, HClO4; (e) LiAlH 4, dry Et2O; (f) 1,5-d 1,5-diborom iboromo o pentan pentane, e, K 2CO3, dry acetone; acetone; (g) CH3I, NaH, dry THF.


Analgesics · Anti-inflammatories · Antiphlogistics · Antirheumatic Drugs

DMSO 2-OCH3-PCP (3 mg/kg)

8

2-OCH3-PCP (6 mg/kg) y c n e t a l k c i l f l i a T

7 6 5 4 3 2

5

10

15

20

25

30

Time (min)

Fig. 1: Mean tail flick latencies in animals that receiving 2-OCH 3PCP i.p. The tail-flick test was conducted 2, 5, 10, 15, 20, 25 and 30 min after injection. Each point represents mean ± SEM of 5 animals.

Saline Ketamine (6 mg/kg)

8

Ketamine (1 mg/kg) Ketamine (0.5 mg/kg)

7 y c n e t a l k c i l f l i a T

6

form. Therefore, the concentration of ketamine in the lipid phase is several orders of magnitude greater than in the aqueous aqueous pha phase se.. Ke Ketam tamine ine gained gained acc access ess to a blocker site associated with the lipid membrane of the lipid protein interface [35]. On the other hand, the predominanc domi nance e of clos closed-c ed-chann hannel el bloc blockade kade sugge suggests sts that ketami ket amine ne’’s ana analge lgesic sic pro proper pertie tiess mig might ht re resul sultt fro from m closed-channel rather than open-channel blockade. 2-OCH3-PC -PCP P has a pol polar ar str struct uctur ure; e; the there refor fore, e, the conce con centr ntrati ation on of thi thiss dru drug g in the aqueous aqueous pha phase se is greater than in the lipid phase, and its analgesic properties might res result ult from open-channe open-channell bloc block k impe impeding ding ionic flow. This may explain why 2-OCH3-PCP has a rapid analgesic effect (5-10 min after injection) on acute and phasic pain. The acute analgesic effect of ketamine is closely associated with sensory and locomotor side effec eff ects ts.. The These se mot motor or sid side e eff effect ectss ar are e inc incre rease ased d de de-pending on the dose, limiting the use of ketamine in chronic pain [34]. At the doses used in this study, 2OCH3-PCP did not show motor side effect. In conclusion, the present study demonstrates that the test compound, synthesized by different by a different method in comparison with previous methods [24, 25] with higher yield and purity, attenuates acute pain in the tail-flick test, possibly exerting its antinociceptive effects through NMDA receptor blockade. Acknowledgements Acknowledgeme nts This work was done as a project at Tehran University, Department me nt of Sc Scien ience ce and I.B I.B.B .B.. (I (Ins nstit titute ute of Bi Bioc ochem hemist istry ry and Biophysi Biop hysics) cs).. The author would like to than thank k Mrs Mrs.. Mahs Mahshid hid Shafiezadeh Shafiezade h and Mrs. T. Yousefifar ousefifard d for their assistance with the pharmacological tests.

5 4 3 2

5

10

15

20

25

30

Time (min) Fig. 2: Average latencies of heat-induced tail-flick responses 2, 5, 10, 15, 20, 25 and 30 min after the i.p. administration of saline or ketamine (0.5, 1, 6 mg/kg). Each point represents the mean ± SEM of 5 animals [1].

4. Discussion Electrophysi Electro physiologi ologicc and bind binding ing stud studies ies rev revealed ealed that vario va rious us ant antago agonis nists ts of NM NMDA DA re rece cepto ptors rs,, inc includ luding ing phencyc phen cyclidin lidine, e, keta ketamine mine and dizoc dizocilpin ilpine e (MK(MK-801) 801),, bind to the PCP site mainly when the channels are in the open or activated state [3, 33]. Previous studies suggest that ketamine may interact with the NMDA receptor at two pot potent ential ially ly dis distin tinct ct sit sites: es: one sit site e loc locate ated d within the channel pore and a second site associated with the hydropho hydrophobic bic domain of the protein. The binding of the agonist to the receptor is assumed to modify the binding of ketamine to both sites. Ketamine is formulat mu lated ed as a hyd hydroc rochlo hlorid ride e sal saltt and thus is hig highly hly water-soluble water-solub le [34], but under physiological conditions, a large fraction of the drug exists in the lipid-soluble Arzneim.-Forsch./Drug Res. 56, No. 5, 346 −350 (2006)  ECV · Editio Cantor Verlag, Aulendorf (Germany)

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Synthesis with Improved Yield and Study on the Analgesic Effect of 2-Methoxyphencyclidine

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