(1: 2: 2: 6: 6-Pentamethylpiperidine), A
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Brit. J. Pharmacol. (1958), 13, 339. PHARMACOLOGICAL PROPERTIES OF PEMPIDINE (1: 2: 2: 6: 6 - PENTAMETHYLPIPERIDINE), A NEW GANGLION - BLOCKING COMPOUND BY S. J. CORNE AND N. D. EDGE From the Research Laboratories, May & Baker Ltd., Dagenham, Essex * (RECEIVED JuNE 27, 1958) Pempidine (1: 2: 2: 6: 6-pentamethylpiperidine) is a long-acting ganglion-blocking compound which is effective by mouth. By intravenous injection it has a similar potency to hexamethonium on the preganglionically stimulated nictitating membrane of the cat. The compound blocks the effects of intravenous nicotine and of peripheral vagal stimulation on the blood pressure; it also causes dilatation of the pupil after removal of the sympathetic innervation. On the guinea-pig ileum, the predominant effect of the compound is to inhibit nicotine contractions. Pempidine is well absorbed from the gastro-intestinal tract as judged by (a) the low ratio (6.9) of oral to intravenous toxicities, (b) the rapid development of mydriasis in mice after oral administration of small doses, and (c) the rapid onset of hypotension when the compound is injected directly into the duodenum of anaesthetized cats. Other actions include neuromuscular paralysis of curare-like type when large doses of the compound are injected intravenously and central effects such as tremors which occur with near toxic doses. In cats with a low blood pressure, large intravenous doses have a slight pressor action. Until recently ganglion-blocking compounds of has been described independently by Spinks and high potency and specificity were thought to Young (1958). be confined to polymethylene bis-quaternary METHODS ammonium series, such as hexamethonium (Paton Cats were anaesthetized with ether or thiopentone, and Zaimis, 1951) and pentolinium (Mason and which was followed by chloralose (80 mg./kg.). Wien, 1955). The discovery by Stone, Torchiana, Supramaximal rectangular pulses of 0.5 msec. dura- Navarro, and Beyer (1956) that mecamylamine tion were used to stimulate nerves. In addition to was a potent ganglion-blocking compound continuous stimulation at a frequency of 10/sec. of revealed that this property was not dependent on the cervical sympathetic nerve trunk, intermittent the presence of a stimulation at frequencies of 20 or 50/sec. was also quaternary nitrogen atom in the applied for 5 sec./min. The peripheral end of the molecule. Furthermore, mecamylamine, a secon- cut right vagus nerve was stimulated at frequencies of dary amine, was found to be well absorbed from 50/sec. The peripheral stump of the cut sciatic nerve the gastro-intestinal tract and to have a pro- of the cat was stimulated at frequencies of 10/min. longed action. and 50/sec. We have found that several secondary and ter- The superior cervical ganglion was perfused by the tiary amines have potent ganglion-blocking pro- method of Kibjakow (1933) as used by Emmelin and perties and this paper describes the properties of MacIntosh (1956) using double-dextrose Locke solu- one of them, pempidine (1: 2: 2: 6: 6-pentamethyl- tion containing physostigmine salicylate (10-'). The piperidine). preganglionic nerve was stimulated at a frequency of 10/sec. for periods of 3 min. and the samples were assayed against acetylcholine chloride on the blood CH3 Jj(CH3 pressure of the eviscerated cat previously treated with C3 C3 mepyramine and physostigmine. NH3 The responses of the pupil of the cat were deter- This compound was examined as a result of an mined after removal of the ipsilateral superior investigation into the structural cervical ganglion (Mason and Wien, 1955). requirements for The isolated guinea-pig ileum was set up in oxy- orally effective ganglion-blocking compounds with genated Tyrode solution at 37'. Agonists were a comparatively long duration of action (Lee, allowed to act for 30 sec. in a 3 min. cycle and the Wragg, Corne, Edge, and Reading, 1958), and it bath was washed out twice in each cycle. In other 2A 340 S. J. CORNE and N. D. EDGE experiments the method of Trendelenburg (1917) was ganglionically stimulated nictitating membrane. employed. This relaxation was slower in development than Langendorff preparations of the rabbit heart were with hexamethonium (Fig. 1), and, having reached perfused with oxygenated double-dextrose Locke a maximum, recovery was usually very prolonged solution at 37°. Drugs were dissolved in the per- fusate before injection into the arterial cannula. so that often there was only a very slight recovery The isolated rectus abdominis muscle of the frog over a period of 30 min. or more. In an attempt was set up in a bath of oxygenated frog Ringer solu- to follow the course of recovery after an injection, tion at room temperature. we applied intermittent stimulation to the nerve, Mydriatic responses were studied in groups of five but in general it was found that complete recovery albino mice (Edge, 1953). The compounds were of the response did not occur and that a period of administered orally. rest was required before the response returned. The effect on nicotine-induced convulsions was In this respect the experiment illustrated in Fig. 1 studied in groups of 10 albino mice and graphical estimates of the ED50 obtained. Nicotine was in- is not typical since there was practically complete jected intravenously 30 min. after an intraperitoneal recovery of the response with no intervening rest injection of a ganglion-blocking agent. period. In this experiment the time required for The method of Haley and McCormick (1957) was 50% recovery was, after pempidine, about eight used to study the effect of compounds injected intra- times that for hexamethonium. cerebroventricularly in mice, the drugs being dis- The duration of action of pempidine and mec- solved in 0.9% w/v NaCl solution and injected in amylamine on the superior cervical ganglion was volumes of 0.01 to 0.05 ml. also relatively prolonged when they were injected Acute toxicity experiments were performed in into the cannulated lingual artery during occlusion groups of 10 albino mice and rats, and the parameters estimated graphically by the method of de Beer of the external carotid artery. (1945). Having once given an effective intravenous dose Pempidine (1:2:2:6: 6-pentamethylpiperidine) was of one of these long-acting compounds, a further used as the hydrochloride (or, in a few experiments, dose of any ganglion-blocking compound given as the hydrogen tartrate). Mecamylamine was used within a period of 2 to 4 hr. was markedly poten- as the hydrochloride, hexamethonium as the bromide, tiated. It was therefore difficult to obtain valid and pentolinium as the hydrogen tartrate. The doses graded responses. To determine the potency we of these four compounds and of adrenaline hydro- first obtained graded responses to hexamethonium chloride refer to the cation. The doses of the follow- and then gave two injections of the long-acting ing compounds refer to their salts unless otherwise a of at hr. stated in the text: decamethonium iodide, tubo- compound separated by period least 2 curarine and acetylcholine chloride, nicotine hydro- It is with these limitations that we assign, on the gen tartrate, histamine acid phosphate, pilocarpine basis of 13 experiments, a potency to pempidine nitrate, atropine sulphate, mepyramine maleate, of 1.35 times that of hexamethonium. In a series physostigmine salicylate, neostigmine methylsulphate, of five similar experiments mecamylamine had a and phenoxybenzamine [benzyl - 2 - chloroethyl (1 - potency of 1.22. methyl-2-phenoxyethyl) amine hydrochloride]. Pempidine had no stimulant action on the relaxed nictitating membrane in doses up to 8 RESULTS mg./kg. Action on the Superior Cervical Ganglion Bennett, Tyler, and Zaimis (1957) found that, of the Cat after a dose of mecamylamine sufficient to cause An intravenous injection of pempidine or of a partial block of transmission to the nictitating mecamylamine caused relaxation of the pre- membrane, tetanic stimulation of the preganglionic FiG. I.-Cat, 3.40 kg., chloralose anaesthesia. Tracing of response of the preganglionically stimulated nictitating membrane. At first arrow, 56 ,ug./kg. hexamethonium intravenously. At second arrow, 51 pug./kg. pempidine intravenously. Time, 1 min. PEMPIDINE3 341 aline injected intravenously nor to stimulation of the postganglionic nerve (Fig. 3). Effect on Release of Acetyl- ,3 choline.-There was evidence that large doses of pempidine reduced the output of acetylcholine from the perfused superior cervical ganglion during preganglionic stimulation. The results of one experiment are shown graphically in Fig. 4. During periods with no stimulation there was no detect- able acetylcholine present in the samples (less than 3 ng./ml.). The activity in the first two samples collected during stimula- tion was equivalent to 13 and 15 ng./ml. respectively (totally 57 FIG. 2.-Cat, 2.70 kg., thiopentone sodium (10 mg.!kg.) followed by chloralose and 54 ng.). After the injection of (60 mg./kg.) anaesthesia. Upper tracing, blood pressure; middle tracing, 10 mg. of pempidine into the contractions of nictitating membrane stimulated preganglionically for 5, 30, 60, and 120 sec. as indicated. Lowest tracing, time in 30 sec. intervals. At arrow, arterial cannula, the two samples 0.1 mg./kg. pempidine intravenously. Vertical scale, blood pressure (mm. Hg). collected during stimulation, which failed to cause a contraction of the nerve caused a reduced but fully maintained con- nictitating membrane, each con- traction. We have failed to confirm this obser- tained 10 ng./ml. (totally 32 and vation with either mecamylamine or pempidine 31 ng.). However, this is still a although various doses and time intervals after injection have been tested. In our experiments with mecamylamine and pempidine, the contrac- 60 tions of the nictitating membrane waned rapidly as with hexamethonium (Fig. 2). 50. Site of Action.-Pempidine was found to act specifically at the ganglion and not on the nicti- bo tating membrane nor on the itself, postganglionic o 40.