GB2222768A - Analgesic compounds and compositions - Google Patents

Abstract

Analgesic compounds is predicted by determining whether it activates a 5HT receptor which is activated by both 5-CT and 8-OH DPAT e.g. by the method described by Roberts et al in J. Physiol (Lond) (1967) 193, 269-294. The use of Ipsapirone, Buspitone, 8-hydroxy-2(n-propyl-amino)-tetralin, 8-hydroxy-2-(n-propylamino)-tetralin, 1-(3-cholorophenyl)-piperazine; 1-(3-trifluoro-methyl-phenyl) piperazine and several further piperazine derivatives as analgesics is dislosed.

Description

ANALGESIC COPlPOUNDS AND COMPOSITIONS This invention relates to the use of 5HT l-like agonists as analgesics. In particular, the invention provides the use of 5HT l-like agonists (including functional equivalents thereof) in the manufacture of analgesic medicaments, methods of analgesic treatment using 5HT l-like agonists, and methods of predicting analgesic activity of a compound by determining whether it is a 5HT l-like agonist.

morphine in various forms has been used to suppress pain perception (i.e. as an analgesic) for about 3,000 years. Even today, morphine and relate opioids remain the most potent and frequently used of the analgesics . However, these drugs have serious adverse side effects which limit teir use. To varyin extents, they are addictive, severely affect gut utility, and depress respiration to a dangerous degree. Further, patients become adapted to them requiring ever increasing doses to obtain relief. The drugs are abused by those who become addicted to the and hence their availability is restricted.

It will be appreciated from the above that there exists a long-established need for a strong analgesic which does not have the adverse side effects of the opioid analgesics. An object of this invention is to provide a class of analgesic compounds of which at least sore do not exhibit said adverse side effects.

It is known that iontophoretically applied 5-hydroxytryptamine (serotonin; 5HT) excites some spinal dorsal horn cells and also inhibits lamina V cell responses to high threshold cutaneous stimuli.

Several workers have reported that iontophoretically applied antagonists of 5HT potently block the excitatory effects of 5HT but are ineffective in blocking the inhibitory effects of 5HT (eg. Belcher et al, Brain Res. (1978) 151, 307-321). Intrathecal antagonists have variously been reported to be effective or not but there is a wide consensus of opinion that systemically administered antagonists potently reduce the effects of morphine and brain stimulation.

In 1982, Beitz (J. eurosci. (1982) 2, 829-842) reported that afferents fro ventrolateral periaqueductal gray (PAG) contained 5T and projected to serotonergic nucleus raphe magnus (NORM) cells.

Llewelyn et al (Brain Res. (1983) 258,59-68) reported in 1983 that 5HT potently excited NRE. cells, that antagonists easily abolished this response and that 5HT releasers and uptake blockers mimicked this effect of 5HT. When uptake blockers were microinjected into the NRt: of unanaesthetised rats, a potent analgesic effect was seen. They proposed that there was an excitatory 5HT input to NRDi from PAG which was very sensitive to 5lIT antagonists.

Functional 5HT receptor subtypes have been classified by Bradley et al (Neuropharmacology (1986) 25, 563-576) as 5HT l-like, 5HT 2 and 5HT 3. The latter has not yet been demonstrated in the brain but central functional receptors are similar (but not identical) to the 5HT 1 and 5HT 2 binding sites reported by Peroutka and Snyder (Fed. Proc. (1983) 42, 213-217). The 5HT 2 receptor has been shown by Davies et al I (Br J. Pharmac (1987) in press) to be responsible for excitation of NRM cells and this response is potently blocked by the selective 5T 2 antagonist ketanserin. 5HT l-like receptors which are resistant to most 5HT 2 antagonists have been shown by Davies et al II (Br J.Pharmac (1987) in press) to be responsible for the inhibitory effects of 5EiT in the central nervous systen (CNS). It is believed that there are two subtypes of SHT-1 receptors, namely 5HT 1A and 5HT 1B. 5HT iA receptors are activated by 5-carboxamidotryptamine (5CT) and & hydrox-2- (n-propylaminc) tetralin (8-OH DPAT), whereas 5HT 1B receptors are activated by 5CT but not 8-OH DPAT.

Abstracts of Davies et al I and II have been published (Br J. Pharmac (1985) 85:255P; (1985) 86:594P; and (1986) 89:526P).

It has now been found that 5HT l-like agonists, especially 5HT 1A agonists exhibit potent analgesic activity. This is surprising in view of the report by Berge et al (Neurosci. Lett. (1985) 54, 71-75, 1985) that 8-OH DPAT antagonised the analgesic action of morphine.

In this specification, including the claims thereof, the terms "5HT l-like agonist" and "5HT 1A agonist" are used to include functional equivalents thereof.

Morphine and other opioid analgesics are not 5HT l-like agonists but produce an analgesic effect by action at an opioid receptor. Accordingly, compounds producing an analgesic effect by action at a 5HT l-like receptor should be free of the serious adverse effects of the opioid analgesics.

According to a first aspect of the present invention, there is provided the use in the manufacture of an analgesic medicament of a 5HT l-likc agonist which has not previously been reported to have analgesic activity and which passes the blood brain barrier.

In a second aspect, the present invention provides a method of providing an analgesic effect in a patient suffering pain other than migraine headache, which comprises administering to the patient an analgesic effective amount of a said 5HT l-like agonist.

According to a third aspect of the present invention there is provided a method of predicting analgesic activity of a compound by determining whether it is a 5HT l-like agonist.

Preferably, the 5HT l-like agonist is a 5T-1A agonist, i.e. one which-activates a 5HT l-like receptor which is activated by both 8-OH DPAT and 5CT.

Compounds can be tested to ascertain whether or not they are 5HT l-like agonists by the method described by Roberts et al in J. Physiol. (Lond) (1967) 193 269-294 and Davies et al I & II (supra). Briefly stated, the method employs a multibarrelled micropipette to determine by, an in vivo microiontophoretic technique, the location of SUT 1-like receptors in the rat brainstem. Action potentials are observed on an oscilloscope whilst manipulating the micropipette to locate neurones in the brainstem. 5HT is iontophoretically released from a barrel of the micropipette into the extracellular environment of the neurone and the oscilloscope observed to ascertain whether the neurone IS excited or depressed. All the careful checks described by Davies et al I & II (supra) are then made to determine that the effects are via a pharmacological receptor and not due to nonspecific direct actions upon the cell membrance. If the cell is depressed, 8-OH DPAT or 5CT is then iontophoretically released from another barrel of the micropipette and the response observed in the oscilloscope. If greater depression than that caused by 5HT is observed with 5CT, the receptor is a 5HT l-like receptor. If the receptor also responds to 8-OH DPAT, it may be a 5HT 1A receptor but if it does not respond to 8-OH DPAT, it may be a 5HT 1B receptor.The compound under test can then be iontophoretically released from the micropipette to determine, by observation of the oscilloscope, if it behaves like a SILT l-like agonist and specifically a 5HT 1A agonist.

In order for a 5HT l-like agonist to be of potential pharmaceutical use, it must pass the blood brain barrier. This may be determined by administering the agonist subcutaneously and observing the action potentials on the oscilloscope as described above. It may also be administered in radiolabelled form and its penetration to central nervous tissue determined by autoradiographical techniques.

Analgesic activity can be determined by subjecting the 5HT 1-like agonists to a conventional rat tail-flick test (see Example 2).

It is believed that 5HT l-like agonists such as Ipsapirone; Buspircne; 8-OH DPAT; 8-methoxy DPAT; 2-hydroxy-N,N-di-n- propylphenethyl- amine; l-(3-chlorophenyl) piperazine; l-(3-trifluoromethyl-phenyl) piperazine; 1-(2- methoxyphenyl) piperazine; piperazinyl-6- chloropyrazine (K-212); l-phenyl piperazine; l-naphthyl piperazine; 4,(3l-tri-fluoromethyl- phenyl)-l [2(4-aminophenyl)ethyl)] piperazine (LY-165163); Gepirone;Nonaperone; 3a,4,5,6,7,7a-hexahydro-2- [4-[4-(2-pyrimidinyl)-1piperazinyl) butyl]-4,7-methano-lH-isoindole-1,3- (2H)-dione dihydrogencitrate (St1-3997); XJy 47846 and 9-[3-(3,5-cis-dimethyl piperazine) propyl] carbazole also will exhibit analgesic activity to a greater or lesser extent. 5CT is unlikely to be of use because it is expected not to pass the blood brain barrier.

5HT 1-like agonists, can be used to treat any condition requiring analgesic to suppress pain perception and in particular can be used as a substitute for opioid analgesics. Thus, they can be used for human or veterinary treatment of any painful condition resulting from disease, injury, surgery or any form of trauma. Examples of pain to be treated by the compounds of the invention include chronic pain, intractable pain, pain subject to spontaneous remission, post-operative pain, phantom lirr.S pain, vascular headache, and the like pain.

It also is believed that 5HT l-like agonists will be of use in alleviating the symptoms of opioid drug withdrawal.

The 5HT l-like agonists can be administered in various manners to achieve the desired analgesic effect. The compounds can be administered enterally, parenterally, or topically, to the patient being treated. Oral administration is likely to be the preferred route in most circumstances but injection intramuscularly, subcutaneously, intravenously or into other tissue will be preferred in some circumstances.

Intrathecal injection directly into the sub or supra arachnoid spaces of the spinal cord may be preferred for presurgical medication, postoperative trauma, childbirth and certain other conditions. Topical application to the skin or the buccal or anal mucosa may be used for local or general pain, inflamation or irritation.

The amount of compound administered will vary and can be any analgesic effective amount. Depending upon the patient and the mode of administration, the quantity of compound administered may vary over a wide range to provide, for example, from about 0.01 itg/kg to 20 mg/kg, usually 0.1 mg/kg to 10 mg/kg of body weight of the patient per unit dose. Unit doses of these compounds can contain, for example, from about 1 mg to 500 mg, usually 10 to 100 mg, of the compound and may be administered, for example, from 1 to 4 times daily.

The term "unit dosage form" is used herein to mean a single or multiple dose form containing a quantity of the active ingredient in admixture with or otherwise in association with a diluent or carrier, said quantity being such that one or more predetermined units are normally required for a single therapeutic administration. In the case of multiple dose forms such as liquids or scored tablets, said predetermined unit will be one fraction, such as a 5 ml (teaspoon) quantity of a liquid or a half or quarter of a scored tablet, of the multiple dose form.

The pharmaceutical formulations in which form the active compounds of the invention will normally be utilized are prepared in a manner well known per se in the pharmaceutical art and usually comprise at least one active compound in admixture or otherwise in association with a pharmaceutically acceptable carrier or diluent therefor. For making those formulations the active ingredient will usually be mixed with a carrier, or diluted by a diluent, or enclosed or encapsulated in a capsule, sachet, cachet, paper or other container. A carrier or diluent may be solid, semi-solid cr liquid material which serves as a vehicle, excipient or medium for the active ingredient. Suitable carriers or diluents are well known per se.

The formulations may be adapted fcr enteral or parenteral use and may be administered to the patient in the form of tablets, capsules, dragees, suppositories, syrups, suspensions or the like.

Alternatively, the formulations may be adapted for topical application to the skin or mucosal surface and examples of such formulations are ointments, gels, creams, impregnated dressings, sprays or inhalants.

The formulations may be in delayed or sustained release form.

Aside from the active agents the compositions may contain pharmaceutically inert organic or inorganic adjuvants, optionally granulating agents, binding agents lubricants, dispersing agents, wetting agents and preservatives. Moreover, the pharmaceutical compositions may contain colouring, flavouring and sweetening substances. Adjuvants for the production of tablets may be e.g. calcium carbonate, lactose micro-crystalline cellulose, mannitol or talc. Starch and alginic acid or micro-crystalline cellulose may be used as granulating and disintegrating agents, starch, polyvinylpyrrolidone and gelatine may be used as binding agents and magnesium stearate, stearic acid, colloidal silica and talc as lubricants. Tablet formulation may be coated or uncoated, the coating having the purpose of delaying the disintegration and absorption in the gastrointestinal tract. Suitable suspending agents for the;production of liquid administration forms are e.g. methyl cellulose and sodium alginate. Capsule formulation may contain the active agents on their own or together with an inert solid diluent e.g. calcium phosphate, corn starch, lactose, or mannitol.

The invention is illustrated in the following non-limiting Examples.

EXAMPLE 1 The effects of the test compound are studied on rat brainstem neurones in vivo during 80 hours of recording. Eight male Nlistar rats are used under halothane anaesthesia. All drugs are applied by microiontophoresis using a multibarrelled micropipette as described in Roberts et al (J. Physiology, 193, 1967).

EFFECTS OF TEST COMPOUND ON CELLS EXCITED BY 5HT Previous studies have shown that the excitatory effects of 5HT on brainstem neurones are only occasionally and weakly mimicked by the 5HT l-like agonist 5CT and not blocked by the 5HT 3 antagonist MDL 72222 or the alpha 1 antagonist prazosin.

Excitatory responses to 5HT are amenable to antagonism by methysergide. The 5HT 2 antagonist, ketanserin, has potent local anaesthetic activity on these cells, but on several units it was possible to selectively attenuate the excitatory effects of 5E'T. Thus, the excitatory effects of 5HT do not appear to involve 5HT l-like, 5HT 3 or alpha 1 receptors but may be due to an action of 5HT on 5HT 2 receptors.

The effects of the test compound are examined on 10-20 cells excited by 5HT.

EFFECTS OF TEST COMPOUND ON CELLS DEPRESSED BY SHT Previous studies have shown that the depressant effects of 5HT are resistant to antagonism by ketanserin and MDL 72222 and, therefore, do not appear to involve either 5HT 2 or 5HT 3 receptors. The depressant effects of 5HT are, however, potently mimicked by 5CT and 8-OH-DPAT suggesting that 5HT l-like receptors are involved in this response, and in particular the 5HT 1A subtype.

The effects of the test compound are examined on 10-20 cells.

EXAMPLE 2 This Example illustrates the confirmation of analgesic activity of test compounds established 5HT l-like agonists by the procedure of Example 1.

Two groups of 5 male Wistar rats are studied. A first rat is placed into a 7 cm diameter glass tube for 1 minute and returned to the home cage for 9 minutes during which time a second rat is placed into the glass tube and the process is repeatedly cycled through 10 rats for more than 2 hours. During the period in the tube, the tail of the rat is laid over a wire coil at room temperature and a low voltage current is then passed through the wire coil sufficient to raise the temperature of the coil by 9.1-C. per second.

After approximately 3 seconds, the temperature of the coil reaches 42-45eC which can be subjectively determined by the experimenter to be a noxious temperature. At about this time the rat flicks the tail away from the coil and the precise latency of the tail-flick is recorded. This latency is a linear index of the temperature which the rat detected as noxious.

When 3 tail-flick latencies have been determined for each rat, each rat receives a coded subcutaneous injection. One group receives 2 mg/kg test compound and one group receives 2 mg/kg of morphine. The measurement of tail-flick latencies is continued.

The measured tail-flick latencies insseconds is recorded and the results presented a graph of average "Index of Analgesia" against time post-injection. The Index of Analgesia is calculated according to the formula: Tail-flick latency - control TFL T - control TFL where control TFL is the average of the 3 tail-flick latencies of the rat taken before injection of the drug and T is the maximum number of seconds that the experimenter allows the tail to remain in contact with the coil in the absence of a tail flick reflex (this is necessary to prevent damage to the tail of rats that are insensitive to painful stimuli). The index of analgesia produces data that can be averaged + s.e.

between animals within a group. An index of 0 means no change from control latencies, and an index of 1 means maximum detectable insensitivity to noxious heat.

EXAMPLE 3 This experiment is conducted in order to establish if the test compound is acting on pharmacological receptors with similar characteristics to those affected by morphine (opioid receptors). Naloxone (i.e. 4,5-epoxy-3,14-dihydroxy-17-(2-propenyl) morphinan-6-one) at a dose of 1 mg/kg is known to prevent drug actions at opioid receptors. Animals were pretreated with this drug but otherwise the procedure is as in Example 2.

EXAMPLE 4 Cne characteristic of drugs acting at opioid receptors is the development of tolerance. If morphine is administered daily then after 7 days or more, depending upon the dosing schedule, morphine has only a very weak analgesic effect (tolerance). Furthermore, all other drugs acting on opioid receptors also have much weaker effects (cross tolerance). This experiment gives rather different information from the experiment with naloxone because it gives insight into the nature of the physiologIcal systems rather than just the pharmacological receptors which are activated by the drugs. If chronic dosing with morphine reduces the level of activity of cells which may be activated by either morphine or another drug, then a cross tolerance experiment will show the interaction between the two.

For these reasons cross tolerance between morphine and the test compound is sought.

Animals are given 2 mg/kg s.c. morphine (n=5) or test compound (n=5) and the tail-flick latencies determined as in Example 2. During the following week, half of these animals receive daily s.c. inject ions of saline and the other half daily doses of morphine. The morphine doses are progressively increased according to the schedule 5, 6, 7, 8, 10, 12, 15 mg/kg/day. On the 8th day all animals received s.c. injections identical to those given on the first day of the experiment and the tail-flick latency is determined as before.

Claims (5)

1. A method of predicting analgesic activity of a compound by determining whether it is an agonist of a SHT receptor which is activated by both 5CT and 8-OH DPAT.

2. A method as claimed in Claim 1, wherein said agonist is a 5HT 1A agonist determined by the method of Roberts et al (J. Physiol. (Lond) (1967) 193 269-294) substantially as described herein.

3. The use in the manufacture of an analgesic medicament of an agonist of a SHT receptor which receptor is activated by both 5CT and 8-OH DPAT and which agonist passes the blood brain barrier and has not previously been reported to have analgesic activity

4. A use as claimed in Claim 3, wherein said agonist is a SHT 1A agonist determined by the method of Roberts et al (J. Physiol. (Lond) (1967) 193 269-294) substantially as described herein.

5. A use as claimed in Claim 3, wherein the agonist is selected from Ipsapirone; Buspirone; 8-GH DPAT; 8-methoxy DPAT; 2-hydroxy-N,N-di-n-propylphenethyl- amine; l-(3-chlorophenyl)piperazine; l-(3-trifluoro- methyl-phenyl)piperazine; l-(2-methoxyphenyl) piperazine; piperazinyl-6-chloropyrazine (MK-212); l-phenyl piperazine; l-naphthyl piperazine; 4,(3'-tri-fluoPzmethyl-phenyl)-1-[2(4-aminophenyl)- ethyl)] piperazine (LY-165163); Gepirone; Nonaperone, 3a,4,5,6,7,7a-hexahydro-2-[4-[4-(2-pyrimidinyl)-1- piperazinyl) butyl]-4,7-methano-lH-isoindole-1,3- (2H)-dione dihydrogencitrate (SM-3997); Wy 47846 and 9-[3-(3,5-cis-dimethyl piperazine) propyl] carbazole.