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Home , Afloqualone, Chlormezanone

PHARMACOLOGICAL STUDIES ON 6-AMINO-2- FLUOROMETHYL-3-(O-TOLYL)-4(3H)- (), A NEW CENTRALLY ACTING (I)

Takashi OCHIAI and Ryuichi ISHIDA Safety Research Laboratory, Tanabe Seiyaku Co. Ltd., 16-89, Kashima-3-chome, Yodogawa-ku, Osaka 532, Japan

Accepted March 1, 1981

Abstract-Neuropharmacological actions of afloqualone were studied in experimental animals. The dose ratio of loss of righting reflex/muscle relaxant activity of afloqualone in mice was larger than those of , , and . Afloqualone, like tolperisone, me

phenesin, and , inhibited the ipsilateral flexor reflex, but not the patellar reflex. In decerebrate cats, the inhibitory activities of aflo

qualone and tolperisone on the polysynaptic spinal reflex were reduced to about 1/5 as compared with those in intact preparations, though the activities of diazepam and mephenesin were almost equal in the both

preparations. In spinal preparation, the inhibitory activities of afloqualone, tolperisone, and mephenesin were almost equal to those in decerebrate

preparations whereas that of diazepam was reduced to about 1/10 as compared with that in decerebrate preparation. Afloqualone and tolperisone inhibited not only the efferent ƒÁ-discharges but also the increment and decrement of patellar reflex by stimulation of the lateral and medial reticular formation. These results suggest that the mode of action of afloqualone is different from the actions of mephenesin, chlormezanone, and diazepam. However, afloqualone, unlike tolperisone, showed no influence on the neuro-muscular transmission and inhibited little the muscle spindle discharges.

In early studies (1, 2) we found that 6 used. The used here were as follows: amino-2-fluoromethyl-3-(o-tolyl)-4(3H) mephenesin (Chugai), chlormezanone (Dai quinazolinone, afloqualone, has potent muscle ichi), tolperisone hydrochloride (Nippon relaxant activity and is lower in neurotoxicity, kayaku), (3), diazepam (Takeda), as compared with its analogues. hydrochloride (Sankyo), chlor In this paper, further pharmacological promazine hydrochloride (Shionogi), a investigations were made in order to elucidate (Nakarai), and urethane (Kata the site and mode of action of afloqualone. yama). Afloqaulone was suspended in 0.5% carboxymethylcellulose sodium salt for p.o. MATERIALS AND METHODS administration or dissolved in physiological Male dd-Y mice weighing 18 to 22 g and saline by adding a proper amount of 1 N cats of either sex weighing 2.2 to 2.8 kg were HCI solution for i.v. administration. Tolperisone was dissolved in physiological drugs. ED50 (LRR) was calculated from the saline. Mephenesin and chlormezanone were number of mice which lost the righting reflex dissolved in physiological saline by adding a for more than 20 sec. proper amount of polyethyleneglycol (#400). Spinal reflexes Without special mention, groups of 6 animals 1. Monosynaptic spinal reflex (patellar were used. ED50 values were calculated by reflex): Cats were spinalized (at C, level) the probit method. Statistical analyses were under ether anesthesia and maintained with performed using Student's t-test. artificial respiration throughout the experi Muscle relaxant activity (motor co-ordina ment. The left hind limb was anchored by tion) a stainless steel bolt through the femur. The Muscle relaxant activity after p.o. admin knee jerk was elicited mechanically at 30 sec istration of the drugs was studied in mice intervals with a rubber hammer operated by as follows: magnetic power. The reflex was recorded on 1. Rotating rod test (RR-test): Mice were a polygraph pen-recorder (Nihon Kohden, placed on a horizontal wooden rod with a RM-1 50) via a force-displacement transducer diameter of 3.5 cm and rotating at the rate of (Nihon Kohden, SB-1T). The drugs were 7.5 r.p.m. This rod was 40 cm above the injected through a polyethylene tube which floor. The mice which remained on the rod had been inserted into the jugular vein. In for more than 1 min in two successive trials addition, blood pressure was recorded on a were selected beforehand. ED50 (RR) was polygraph pen-recorder via a transducer calculated from the number of mice which (Nihon Kohden, PR-3) attached to a cannula failed to remain on the rod for 1 min at 1 hr which had been inserted into the right after administration of the drugs. common carotid. The actual experiments 2. Traction test (TR-test): Mice were were not started until 2 hr had elapsed after suspended by their forelimbs on a horizontal, the termination of ether anesthesia. stainless steel bar with a length of 15 cm and 2. Polysynaptic spinal reflex: a diameter of 1.5 mm. The rod was 30 cm 2.1. Ipsilateral flexor reflex: Intact (a above the floor. The mice which could put chloralose 60 mg/kg i.p.), spinal (at C, level), either hind paw on the wire within 10 sec and decerebrate (intercollicular-prepontine) were selected previously. ED50 (TR) was cats (4, 5) were used. The flexor reflex of calculated from the number of mice which the anterior tibialis was elicited by electrical failed to put either hind paw on the wire stimulation of the ipsilateral peroneal nerve within 20 sec at 1 hr after the drugs. (1 msec, 0.2 Hz, and 1.5 to 2.0 volt). In 3. Inclined screen test (IS-test): Mice hibitory effects of the drugs on the reflex were placed on a canvas screen (50x60 cm) were expressed by the following formula; inclined at an angle of 30° from the floor. [1 -(mean amplitude for 3 min in the maximal The mice which remained on the screen for inhibitory period after the drugs/mean ampli more than 1 min in two successive trials were tude for 3 min before the drugs)] x 100. selected beforehand. ED50 (IS) was Other experimental conditions were the calculated from the number of mice which same as mentioned above. failed to remain on the screen for 1 min at 2.2. Ipsilateral hind-limb withdrawal reflex: 1 hr after the drugs. The spinal cord was transected at the Th_,o Loss of the righting reflex (LRR) activity level, with the mice under ether anesthesia. Mice were laid gently on their backs on a Twenty four hr later, the mice which showed table 1 hr after p.o. administration of the lifting up or shaking a hind foot immersed into the water at 50°C were selected and pletion of all surgery, cats were immobilized used in groups of eight. The latent period with (20 mg/kg i.m.), until the appearance of the reflex was anesthetized with a-chloralose (40 mg/kg measured 1 hr after the drugs. The reflex of i.p.), and maintained with artificial respiration the intact mice was also examined similarly. throughout the experiment. -( Efferent Increment and decrement of the patellar discharges from filaments of L7 ventral root reflex by stimulation of the facilitatory and were recorded by a universal dual-beam inhibitory area of the brainstem reticular oscilloscope (Nihon Kohden, VC-9) via a formation biophysical amplifier (Nihon Kohden, AVB-9) Cats were anesthetized with a-chloralose and a long recording camera (Nihon Kohden, (60 mg/kg i.p.) in combination with urethane PLG-6106). The bipolar silver-silver chloride (0.5 g/kg s.c.) and fixed in a stereotaxic electrode was used for the recording. Neuro apparatus (Tokyo Univ. Brain Res. Inst.). physiological identification of r-motoneuron The left hind limb was anchored by a stainless was carried out on the basis of the criteria of steel bolt through the femur. The patellar Granit (4, 5) and Ginzel et al. (7). All the reflex was elicited mechanically 3 times per drugs were given into the jugular vein. 10 sec with a rubber hammer operated by Muscle spindle discharges magnetic power. Bipolar stimulating The procedure of laminectomy in cats was electrodes were acutely inserted into the carried out in the same manner as in the test mesencephalic facilitatory [F: 0-3, L (right): on the -r-efferent discharges. After lami 3-4.5, and H: (-3)-2] and medullary in nectomy, the left hind limb was denervated hibitory [P: 10, L (right) : 1, and H : (-9) except the nerve innervating the triceps sural (-7)] area according to the brain atlas of muscle and which was stretched using a wt. Snider and Niemer (6). The increment and of 200 g and a string connected to Achilles's decrement of the patellar reflex by stimulation tendon cut away from the calcaneum. After (1 msec, 100 Hz, and 3-5 volt for 30 sec) of completion of all surgery, the muscle spindle the facilitatory and inhibitory area were discharges from filaments of L7 dorsal root recorded on a polygraph pen-recorder via a were recorded as mentioned above. force-displacement transducer. The drugs Neuro-muscular junction were injected through a polyethylene tube Cats were spinalized (at C, level) under which had been inserted into the jugular vein. ether anesthesia and maintained with artificial T-Efferent discharges respiration throughout the experiment. The Cats were deeply anesthetized with ether sciatic nerve trunk was completely severed in and fixed in a stereotaxic apparatus. Lamin the sciatic notch. The insulated bipolar ectomy was performed in the lumbosacral stimulating electrodes were placed on the region and the spinal cord was exposed. Both peroneal nerve. The twitch of the anterior ventral and dorsal roots from L5 to S2 were tibialis was recorded on the polygraph pen cut bilaterally and other ventral and dorsal recorder (Nihon Kohden, RM-45) via a force roots were left intact. A skin pouch was displacement transducer. Double pulses (0.1 prepared at the site of dissection in order to msec, 0.2 Hz, and 1.5 to 2.0 volt) were cover the exposed spinal cord with paraffin delivered from the electrical stimulator (Nihon liquid at 36±0.5°C. Rectal temp. was main Kohden, MSE-40) and interstimulus interval tained at 36±0.5°C using a DC heating pad. was gradually increased every 0.1 msec from After laminectomy, intercollicular-prepontine 0.9 msec to maximum 2.0 msec. The re decerebration was carried out. After com fractory period after administration of the drugs was compared with those at 5 min before the drugs. All the drugs were injected through a cannula which had been inserted into the right femoral vein. The actual experiments were not started until 2 hr had elapsed after the termination of ether anesthesia.

RESULTS Effects on motor co-ordination and righting reflex (LRR) Fifty % inhibitory doses of afloqualone and other drugs in the rotating rod, traction, and inclined screen tests and their 50% effective doses of the loss of righting reflex (LRR) are shown in Table 1. The muscle relaxant activity of afloqualone was more potent than those of other drugs. The ratio of LRR50 to ED50 (RR) of afloqualone was the largest of all. Effects on spinal reflexes 1. Monosynaptic spinal reflex (patellar reflex): Neither afloqualone nor tolperisone inhibited the patellar reflex at doses up to Fig. 1. Effects of afloqualone and other drugs on 50 mg/kg i.v. and at a dose of 20 mg/kg i.v., the patellar and ipsilateral flexor reflexes in respectively. Diazepam was also ineffective spinal (at C, level) cats. All these drugs in a dose of 10 mg/kg i.v. On the other hand, inhibited the flexor reflex immediately after baclofen markedly depressed the reflex at a injection. In neither preparation was the patellar reflex affected, except for baclofen. dose of 5 mg/kg i.v. (Fig. 1). B.P.: Blood pressure, ref.: reflex. 2. Polysynaptic spinal reflexes 2.1. Ipsilateral flexor reflexes: decerebrate cats were reduced to about 1 /5 as Intact cats: As shown in Fig. 2, afloqualone compared with those in the intact cats. and other drugs inhibited the flexor reflex However, the activities of diazepam and dose dependently. The doses required to mephenesin were almost equal in the both reduce the amplitude of the flexor reflex preparations (Fig. 2). before the drugs by 50% were approx. 0.8 mg/ Spinal cats: Afloqualone and other drugs kg i.v. in afloqualone, 9.5 mg/kg i.v. in inhibited the flexor reflex dose dependently. mephenesin, 1.4 mg/kg i.v. in tolperisone, The inhibitory effects of afloqualone, me and 0.04 mg/kg i.v. in diazepam, respectively phenesin, and tolperisone in spinal cats were (Fig. 2). equal to those in decerebrate cats, re Intercollicular-prepontine decerebrate cats: spectively. On the other hand, the inhibitory Afloqualone and other drugs inhibited the activity of diazepam on polysynaptic spinal flexor reflex dose dependently. The inhibitory reflex in spinal cats was reduced to approx. activities of afloqualone and tolperisone on 1 /10 as compared with that in the decerebrate polysynaptic spinal reflex in intercollicular cats (Fig. 2). 495 Fig. 2. Dose-response relationships for afloqualone Fig. 3. Dose-response relationships for afloqualone and other drugs on ipsilateral flexor reflex in and other drugs on ipsilateral hind-limb with intact (a-chloralose 60 mg/kg i.p.), spinal (at drawal reflex in intact and spinal (at Th7-,o level) C, level), and decerebrate (intercollicular mice. Abscissa: dose in mg/kg p.o., ordinate: prepontine) cats. Abscissa: dose in mg/kg i.v., the latent period (sec) until the appearance of ordinate: inhibitory ratio of flexor reflex. Maxi the reflex. Each vertical line indicates the mum S.E.'s are 26.2% in afloqualone, 22.4% S.E. *: p<0.05, **: p<0.01. Mephenesin: in mephenesin, 29.8% in tolperisone, and x 10 dose in mg/kg p.o. n=8 13.7% in diazepam, respectively. n=4 the both preparations (Fig. 3). 2.2. Ipsilateral hind-limb withdrawal reflex: Effects on the increment and decrement of the In intact mice, afloqualone significantly patellar reflex by stimulation of the facilitatory increased the latency of the reflex dose and inhibitory area of the brainstem reticular dependently at doses of 10 to 35 mg/kg p.o. formation Mephenesin and morphine hydrochloride also Afloqualone had no influence on both the exhibited the same effect at doses of 350 increment and decrement of the patellar mg/kg or more p.o. and 5 mg/kg p.o., reflex at doses up to 5 mg/kg i.v. As shown respectively. In spinal mice, the activity of in Fig. 4-a, 10 mg/kg of afloqualone abolished afloqualone was reduced to about 1/5 as the increment of the reflex, but not the compared with that in intact mice whereas decrement. The marked inhibition of both morphine hydrochloride was inactive even at the increment and decrement of the patellar a dose of 35 mg/kg p.o. However, the reflex was observed at 20 mg/kg i.v. of activity of mephenesin was almost equal in afloqualone and lasted for more than 2 hr. Fig. 4. Effects of afloqualone and other drugs on both the increment and decrement of the patellar reflex by stimulation of the facilitatory (BF) and inhibitory (BI) area of the brainstem reticular formation.

Tolperisone (20 mg/kg i.v.), mephenesin Effects on muscle spindle discharges (20 mg/kg 1.v.), and chlormezanone (20 and Muscle spindle discharges appeared im 50 mg/kg i.v.) also inhibited both the mediately after the appropriate stretch of the increment and decrement of the reflex (Fig. muscle and lasted during the stretch period. 4-b). However, the actions of tolperisone Five cats were used at each dose of the drugs. and mephenesin were slight and temporary. Afloqualone slightly reduced the discharges Effects on T-efferent discharges in 3 cases out of 5 at a dose of 20 mg/kg i.v. Both afloqualone and tolperisone inhibited whereas tolperisone markedly inhibited the the r-efferent discharges dose dependently discharges in all 5 cases (Fig. 6). at doses of 10 to 20 mg/kg i.v. Inhibitory Effects on neuro-muscular junction activity of afloqualone was equal or somewhat The twitch of the anterior tibialis by double superior to that of tolperisone. stimulation of the peroneal nerve was shown hydrochloride which was used for the in Fig. 7. The refractory period varied identification of the r-neuron filament had a individually between 0.9 and 1.4 msec long-lasting depression even at a dose of (mean±S.E.: 1.16±0.03 msec, n=25) before 0.2 mg/kg i.v. (Fig. 5). the drugs. Five cats were used for each dose Fig. 5. Effects of afloqualone and tolperisone on r-efferent discharges in the intercollicular-prepontine decerebrate cats. Inhibitory effect of afloqualone was equal or somewhat superior to that of tolperisone . of the drugs. In all cases, afloqualone failed dose of 50 mg/kg i.v. (from 1.28±0.04 to to prolong the refractory period, even at a 1.27±0.04 msec). On the other hand, mephenesin, tolperisone, and chlormezanone markedly prolonged the refractory period from 1.14±0.02 msec to 1.28±0 .05 msec, from 1.38±0.06 msec to 1.68±0.04 msec (p<0.05), and from 1.10±0.03 msec to 1.30±0.03 msec (p<0.05) at 20 mg/kg i.v., respectively (Fig. 7).

DISCUSSION The dose ratio of loss of righting reflex/ muscle relaxant activity of afloqualone in mice was larger than those of tolperisone, me phenesin, and chlormezanone. This suggests that the specificity of muscle relaxing action of afloqualone is considerably high as compared with those of other drugs. Afloqualone, like mephenesin, tolperisone, and diazepam, inhibited the ipsilateral flexor Fig. 6. Effects of afloqualone and tolperisone on reflex dose dependently in the intact, spinal, afferent muscle spindle discharges evoked by and decerebrate preparations but not the stretch of triceps sural muscle in cats. Tolperi sone, unlike afloqualone, markedly inhibited patellar reflex, even at considerably higher the afferent discharges. doses. On the other hand, baclofen, unlike these drugs, inhibited both reflexes, to almost tolperisone (10-13), and diazepam (14) is the same degree. These results suggest that substantially different from that of baclofen the mechanism of muscle relaxing action of (15-20). However, Crankshaw and Raper afloqualone as well as mephenesin (8, 9), (21) reported that mephenesin inhibited the

Fig. 7. Effects of afloqualone and other drugs on the twitch response of the anterior tibialis muscle by double stimulation, at various intervals, applied to the peroneal nerve in spinal (at C, level) cats. Only afloqualone failed to prolong the refractory period even at a dose of 50 mg/kg i.v. S and figures indicate a single stimulation and stimulation interval (msec), respectively. monosynaptic spinal reflex potential though it Tolperisone, when given i.v., produced a did not inhibit the patellar reflex. Therefore, marked hypotension at doses which inhibited it cannot be concluded from our results that the polysynaptic reflex, but it neither lowered afloqualone has no inhibitory effect on the the blood pressure nor inhibited the reflex monosynapse. when given p.o. even at higher doses (50 to In anesthetized intact preparations, the 100 mg/kg). This suggests that the in dose required to reduce the amplitude of the hibitory action of tolperisone on the poly flexor reflex before administration of the synaptic reflex, when given i.v., may be drugs by 50% was approx. 0.8 mg/kg i.v. in secondary to its hypotensive action, though afloqualone, 9.5 mg/kg i.v. in mephenesin, there have been reports which refuted this 1.4 mg/kg i.v. in tolperisone, and 0.04 mg/ proposal (11, 28). kg i.v. in diazepam, respectively. In the Afloqualone, unlike tolperisone (29), decerebrate preparation, however, the in mephenesin (21, 29, 30), and chlormezanone hibitory activities of afloqualone and (30), had no influence on the neuro-muscular tolperisone on the polysynaptic spinal reflex transmission and the muscle spindle were reduced to about 1 /5 as compared with discharges, indicating that the mode of those in the intact preparation, though the action on the peripheral motor system differs activities of diazepam and mephenesin were from the actions of tolperisone, mephenesin, almost equal in the both preparations. In and chlormezanone. the spinal preparation, the inhibitory activities Acknowledgements: We are grateful to Dr. of afloqualone, tolperisone, and mephenesin A. Okaniwa, Director of the Safety Research were almost equal to those in the decerebrate Laboratory and Dr. A. Kiyomoto, Director of preparation whereas that of diazepam was Pharmacological Research Laboratory, reduced to about 1 /10 as compared with that Tanabe Seiyaku Co. Ltd., for constant in the decerebrate preparation. In addition, encouragement and pertinent suggestions. afloqualone and tolperisone inhibited not only Thanks are also due to Mr. Y. Kudo and Ms. A. the efferent r-discharges but also both the Ogawa for excellent technical assistance. increment and decrement of patellar reflex by stimulation of the facilitatory and inhibitory REFERENCES area (22, 23) of the brainstem reticular 1) Tani, J., Yamada, Y., Oine, T., Ochiai, T., formation. These results suggest that Ishida, R. and Inoue, I.: Studies on biologically afloqualone and tolperisone may also produce active halogenated compounds. I. Synthesis the inhibitory action on the polysynaptic and central nervous system activi pathways in the higher CNS as compared ty of 2-(fluoromethyl)-3-aryl-4(3H)-quinazoli none derivatives. J. med. Chem. 22, 95-99 with diazepam (24-26) which dominantly (1979) inhibits the polysynaptic pathways in the 2) Tani, J., Yamada, Y., Ochiai, T., Ishida, R., lower brainstem. As there was no marked Inoue, I. and Oine, T.: Studies on biologically difference between intact and spinal pre active halogenated compounds. II. Modifi cations of 6-amino-2-fluoromethyl-3-(o-tolyl)- parations in the inhibitory activities of 4(3H)-quinazolinone and the CNS depressant mephenesin on the flexor reflex in cats and activities of related compounds. Chem. Pharm. on the ipsilateral hind-limb withdrawal reflex Bull. 27, 2675-2687 (1979) in mice supports the idea that the possible 3) Japanese Patent Pub. (Examined) No. 16692 main site of the action of mephenesin (27) (1970) 4) Granit, R.: Receptors and Sensory Perception. is on the polysynaptic pathways of the p. 237, Yale University Press, New Haven (1955) spinal cord. 5) Granit, R.: Receptors and Sensory Perception. p. 369, Yale University Press, New Haven 18) Nistri, A.: Further investigations into the effects

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