WO1998030243A1

WO1998030243A1 - Acetylcholinesterase inhibitors in combination with muscarinic agonists for the treatment of alzheimer's disease

Info

Publication number: WO1998030243A1
Application number: PCT/US1997/023792
Authority: WO
Inventors: Roy Douville Schwarz; Michael James Callahan
Original assignee: Warner Lambert Co LLC
Current assignee: Warner Lambert Co LLC
Priority date: 1997-01-08
Filing date: 1997-12-29
Publication date: 1998-07-16
Anticipated expiration: 1999-07-08
Also published as: AU5716898A; HRP980006A2; CO5011095A1

Abstract

New compositions of matter and a method for treating bodily disorders involving cholinergic hypofunction such as Alzheimer's disease in a mammal are disclosed. The compositions comprise a combination of an acetylcholinesterase inhibitor and a muscarinic agonist. The method comprises administration of the combination to a mammal. The instant invention demonstrates that the combination of an acetylcholinesterase inhibitor and a muscarinic agonist can be safely administered, that doses of each agent which by themselves showed no activity yielded positive responses and minimal side effects in combination, and that the active dose range for both agents could be widened when used in combination. These results imply that the combined treatment may eliminate the need to individually tritrate doses and also increase the separation between efficacy and adverse events.

Description

ACETYLCHOLINESTERASE INHIBITORS IN COMBINATION WITH

MUSCARINIC AGONISTS FOR THE TREATMENT OF

ALZHEIMER'S DISEASE

FIELD OF THE INVENTION

This invention relates to novel compositions and methods for the treatment of Alzheimer's disease and other central and peripheral nervous system disorders involving cholinergic hypofunction.

SUMMARY OF THE RELATED ART

Cognitive disorders, including Alzheimer's disease, are generally accompanied by symptoms of forgetfulness, confusion, memory loss and other symptoms resulting from aging, brain injury, or disease. The concomitant decrease in cognitive function during the aging process has been documented in various mammals, including humans. In particular, presenile and senile primary degenerative dementia appear to be common causes of mental deterioration among the elderly. The symptoms of cognitive disorder appear to be associated with decreased acetylcholine synthesis as well as impairment of the ACh receptive neurons. The activity of the enzyme choline acetyltransf erase (ChAT), which catalyzes the synthesis of acetylcholine from choline and acetyl coenzyme A, can be severely reduced as reflected by the loss of cholinergic (acetylcholine releasing) nerve endings in the hippocampus. Conversely, post-synaptic muscarinic receptors are generally intact. The cholinergic terminals are thus recognized as critically important to memory function.

Alzheimer's disease is a chronic neurodegenerative disorder. With increased life expectancy, the number of Alzheimer's patients can be predicted to rise rapidly in the future. Decline in cognitive function is the cardinal symptom of

Alzheimer's disease, and a beneficial treatment effect on cognitive function is today a sine qua non of efficacy for an antidementia drug. Acetylcholine- synthesizing neurons in the basal forebrain region and their cortical synaptic connections exhibit a well-characterized degeneration in Alzheimer's disease. Thus, most drug research targeting Alzheimer's disease has been focused on providing symptomatic cognitive enhancement by increasing acetylcholine transmission.

Deficits in sustained attention are consistently reported in aged and demented humans (Alexander DA. Psvchol. Rep., 1973;32:229-230.) The role of an attentional deficit and the cholinergic contribution to these deficits may be important in Alzheimer's disease. These deficits in attention are similar to those produced by scopolamine in otherwise cognitively intact humans (Wesnes and Warburton, Neuropsychobiology, 1983; 9:154-157; Wesnes and Warburton, Drug Dev. Res., 1988,12:279-286). Scopolamine has been used in healthy volunteers as a model of dementia to screen for compounds for potential therapeutic usefulness (Wesnes, et al., Ann. NY Acad. Sci., 1991;640:268-271).

Presently, there are three general approaches to enhance cholinergic transmission in the central nervous system. The first approach is to enhance cholinergic neurons by excessive exposure to a form of choline. Such attempts have been mildly successful, but only in the early stages of Alzheimer's disease. The second approach involves postsynaptic direct stimulation of muscarinic receptors by oral or intravenous administration of drugs. This approach is limited because of a low therapeutic index (a high effective dose to toxic dose ratio). In addition, a variety of undesirable, nonspecific side effects would be expected. The third approach involves the inhibition of acetylcholinesterase, the enzyme that metabolizes acetylcholine. At present, Alzheimer's disease is treated by l,2,3,4-tetrahydro-5-aminoacridine (Tacrine) (US Patent No. 4,816,456), a therapy involving inhibition of acetylcholinesterase activity. The most frequent adverse events established during clinical trials of high-dose 1,2,3,4-tetrahydro- 5-aminoacridine were elevated liver transaminase levels, followed by dose-related peripheral cholinergic effects primarily affecting the gastrointestinal tract (nausea, vomiting, diarrhea, dyspepsia, anorexia). The risks of 1,2,3,4-tetrahydro- 5-aminoacridine treatment are small relative to its benefits, but achieving optimal l,2,3,4-tetrahydro-5-aminoacridine treatment response requires careful dose-titration and transaminase monitoring. Accordingly, new compositions and methods for treating diseases resulting from cholinergic hypofunction are desired.

SUMMARY OF INVENTION

The present invention comprises new compositions and methods for treating central and peripheral nervous system disorder involving cholinergic hypofunction. The compositions of the present invention comprise a combination of acetylcholinesterase inhibitors and muscarinic agonists. The methods of the invention comprise the use of these compositions for the treatment of cholinergic hypofunction.

This invention is an improvement over previous compositions and treatment methods because the two agents can be safely and effectively administered in combination using doses of each agent that by themselves showed no activity. Positive results with minimal side effects are obtained with the present composition. The active dose range for the compounds is widened in the present combination. The combined treatment may eliminate the need to individually titrate doses and also increase the separation between efficacy and adverse events. A preferred embodiment utilizes an acetylcholinesterase inhibitor selected from tacrine or donepezil (E2020) and a muscarinic agonist selected from milameline (CI-979), xanomeline (LY246708), or CI-1017.

BRIEF DESCRIPTION OF THE DRAWINGS

A more complete appreciation of the invention and many of the attendant advantages thereof will more readily be understood by reference to the following detailed description when considered in connection with the accompanying drawings, wherein^: Figure 1 shows reversal of scopolamine-induced impairment of continuous performance in rhesus monkeys by administration of 1,2,3,4-tetrahydro- 5-aminoacridine (tacrine).

Figure 2 shows reversal of scopolamine-induced impairment of continuous performance in rhesus monkeys by administration of l-benzyl-4-(5,6-dimethoxy-

1 -indanon)-2-yl)methylpiperidine (E2020).

Figure 3 shows reversal of scopolamine-induced impairment of continuous performance in rhesus monkeys by administration of 1,2,5,6-tetrahydro-l- methyl-3-pyridinecarboxaldehyde-O-methyl-oxime (milameline, CI-979). Figure 4 shows reversal of scopolamine-induced impairment of continuous performance in rhesus monkeys by administration, in combination, of tacrine and CI-979.

Figure 5 shows reversal of scopolamine-induced impairment of continuous performance in rhesus monkeys by administration, in combination, of 1-benzyl- 4-(5 ,6-dimethoxy- 1 -indanon)-2-yl)methylpiperidine (E2020) and CI-979

(milameline).

Figure 6 shows the observable side effects seen upon a 1,2,3,4-tetrahydro- 5-aminoacridine-produced decrease in responses on continuous performance tasks in rhesus monkeys. Figure 7 shows a dose-response decrease in the absence of any observable side effects in responses on a continuous performance task in rhesus monkeys upon administration of 1 -benzyl -4-(5,6-dimethoxy- 1-indanon)- 2-yl)methylpiperidine.

Figure 8 shows a dose-response decrease in responses on a continuous performance task in rhesus monkeys upon administration of CI-979.

Figure 9 shows a dose-response decrease in responses on a continuous performance task in rhesus monkeys upon administration, in combination, of tacrine and CI-979 (milameline).

Figure 10 shows a dose-response decrease in responses on a continuous performance task in rhesus monkeys upon administration, in combination, of

1 -benzyl -4-(5,6-dimethoxy- 1 -indanon)-2-yl)methylpiperidine (E2020) and milameline. DETAILED DESCRIPTION OF THE INVENTION

We have surprisingly discovered that combining an acetylcholinesterase inhibitor and a muscarinic agonist broadened the dose-response effect by significantly reversing a scopolamine-induced behavioral impairment. These results suggest that the combination of acetylcholinesterase inhibitors and muscarinic agonists is useful in the treatment of cognitive dysfunction arising from cholinergic hypofunction, such as Alzheimer's disease. The improved performance with the combination treatment occurred at lower doses than required for either compound alone. This effect at lower doses when given in combination provides a greater separation between the efficacious dose and the dose producing peripheral side effects. No difference in drug plasma levels was observed for either agent when the acetylcholinesterase inhibitor 1,2,3,4-tetrahydro- 5-aminoacridine (tacrine) (U.S. Patent No. 4,816,456) and the muscarinic agonist l,2,5,6-tetrahydro-l-methyl-3-pyridinecarboxaldehyde-O-methyloxime (milameline CI-979) (U.S. Patent No. 5,219,872) were used in combination as compared to when used alone (see Table 1). These results establish that the combined treatment may eliminate the need to individually titrate doses and also increase the separation between efficacy and adverse events.

TABLE 1. Plasma Levels of 1 ,2,5,6-Tetrahydro- 1 -methyl-3-pyridinecarboxaldehyde -O-methyloxime and l,2,3,4-Tetrahydro-5-aminoacridine Alone and in Combination in Adult Rhesus Monkeys Drug Dose, IM Plasma levels Plasma levels (ng/mL)

(mg/kg) (ng/mL) In combination³

1,2,5,6-tetrahydropyridin- 0.003 1.12 (1.27-0.97) 1.35 (1.42-1.28)

3-carboxaldehyde oxime

1,2,3,4-tetrahydro- 0.32 34.4 (41.7-30.3) 29.1 (33.7-24.5)

5-aminoacridine a

Combination: l,2,5,6-Tetrahydro-l-methyl-3-pyridinecarboxaldehyde-O- methyl-oxime (0.003 mg/kg) + l,2,3,4-tetrahydro-5-aminoacridine (0.32 mg/kg) n = 2 except l,2,3,4-tetrahydro-5-aminoacridine alone group was n = 4. In accordance with the foregoing, the present invention comprises a composition of matter comprising the combination of at least one acetylcholinesterase inhibitor and at least one muscarinic agonist. Such acetylcholinesterase inhibitors are well-known in the art and include but are not limited to physostigmine (eserine), monoamine acridines and their derivatives (U.S.

Patent No. 4,816,456), l-benzyl-4-(5,6-dimethoxy-l-indanon)-2-yl)methyl- piperidine (Aricept, donepezil, E2020) (U.S. Patent No. 4,895,841), piperidine and piperazine derivatives (U.S. Patent No. 5,041,455), piperidinyl-alkanoyl heterocyclic compounds (EP 487071), N-benzyl-piperidine derivatives (U.S. Patent No. 5,106,856), 4-(l-benzyl:piperidyl)-substituted fused quinoline derivatives (EP 481429-A) and cyclic amide derivatives (EP 468187). Other typical acetylcholinesterase inhibitors include carbonic acid derivatives such as those described in U.S. Patent No. 5,602,176 (e.g. exelon, ENA-713, which is (S)-[N-ethyl-3-[(l -dimethylamino)ethyl]-N methyl-phenyl-carbamate]), and phosphonate compounds such as O, O-dimethyl-(l-hydroxy-2, 2,2-trichloroethyl) phosphonate (metrifonate, or trichlofon). Benzazepinols such as galantamine are also useful acetylcholinesterase inhibitors.

Similarly, muscarinic agonists are well-known in the art and include but are not limited to arecoline, tetrahydropyridine derivatives such as l,2,5,6-tetrahydropyridin-3-carboxaldehyde oxime, and l,2,5,6-tetrahydro-l-methyl-3-pyridinecarboxaldehyde-O-methyloxime hydrochloride (milameline, CI-979, U.S. Patent No. 5,219,872). Other pyridine derivatives include 3-(3-hexyloxy-l ,2,5-thiodiazsol-4-yl)-l ,2,5,6,-tetrahydro- 1-methylpyridine (xanomeline, LY246708, U.S. Patent No. 5,043,345), and 3-(3-hexylthio-l,2,5-thiadiazol-4-yl)-l,2,5,6,-tetrahydro-l-methylpyridine U.S.

Patent No. 5,041,455). Additional muscarinic agonists include talsaclidine, which is (3R)-3-(2-propynyloxy)quiniclidine, and memric, which is R-(Z)-α-(methoxyimins)-l-azobicyclo [2.2.2] octane-3-acetonitrile, and YM-796, which is (S)-(-)-2,8-dimethyl-3-methylene-l-oxa-8-azaspiro-[4.5]decane L-tartrate monohydrate, (U.S. 4,996,210).

Certain pyridine-like derivatives are aza-bicyclics such as 1-aza-bicyclo [2.2.1] heptan-3 -one-O-[3-(3 -methoxyphenyl)-prop-2-ynyl] oxime (CI-1017, U.S. Patent No. 5,346,911), and 3-(3-butylthio-l,2,5-thiadiazol-4-yl)-l-azabicyclo [2.2.2]-octane. Preferably, the composition comprises one acetylcholinesterase inhibitor and one muscarinic agonist.

In a preferred embodiment, the acetylcholinesterase inhibitor comprises 1 ,2,3,4-tetrahydro-5-aminoacridine or 1 -benzyl-4-(5,6-dimethoxy- 1 -indanon)-

2-yl)methylpiperidine, and the muscarinic agonist comprises 1,2,5,6-tetrahydro- l-methyl-3-pyridinecarboxaldehyde-O-methyloxime or 1-aza- bicyclo[2.2.1]heptan-3-one-O-[3-(3-methoxyphenyl)-prop-2-ynyl]oxime.

As used herein, "acetylcholinesterase inhibitor" and "muscarinic agonist" include their respective pharmaceutically acceptable salts, such as hydrochlorides, tartrates, and the like.

All of the foregoing patents are incorporated herein by reference for their disclosure of typical acetylcholinerase inhibitors and muscarinic agonists.

In a preferred embodiment, the invention comprises a composition of matter wherein the ratio of acetylcholinesterase inhibitor relative to muscarinic agonist is between 0.5:1 and 1000:1 by weight. In a more preferred embodiment, the ratio of acetylcholinesterase inhibitor relative to muscarinic agonist is between 1 : 1 and 500: 1 by weight. In a most preferred embodiment, the ratio is between 3:1 and 350:1 by weight. Aside from their utility for treating cholinergic deficit states, the compositions of the invention are useful research tools for studying the physiology of such states.

In another aspect, the present invention comprises a method of treating central and peripheral nervous system disorders involving cholinergic hypofunction in a mammal, said method comprising administering to a mammal an amount of at least one acetylcholinesterase inhibitor and at least one muscarinic agonist effective in treating the cholinergic hypofunction. As used herein, central and peripheral nervous system disorders involving cholinergic hypofunction include but are not limited to dementias, amnesias, cerebral insufficiencies, and psychiatric disturbances in the central nervous system and neuronal and smooth muscle dysfunction of the gut, bladder, and secretory glands in the peripheral nervous system. The acetylcholinesterase inhibitor(s) and muscarinic agonists(s) can be administered together as a composition, or may be administered separately. If administered separately, such subsequent administration should occur within a time period such that the drugs can act in concert within the body. In a preferred embodiment of the instant invention, the acetylcholinesterase inhibitor comprises 1 ,2,3 ,4-tetrahydro-5-aminoacridine or 1 -benzyl-4-(5 ,6-dimethoxy- 1 -indanon)-

2-yl)mefhylpiperidine and the muscarinic agonist comprises CI-979, CI-1017, or xanomeline.

The present invention is further directed to the method of treating central and peripheral nervous system disorders involving cholinergic hypofunction in a mammal, the method comprising the administration to a mammal of a ratio of acetylcholinesterase inhibitor relative to muscarinic agonist of between 0.5:1 and 1000:1 by weight. In a more preferred embodiment, the ratio of acetylcholinesterase inhibitor relative to muscarinic agonist is between 1 : 1 and 500: 1 by weight. In a most preferred embodiment, the ratio is between 3:1 and 350:1 by weight. The combinations are synergistic for treating Alzheimer's disease.

The compositions of the invention can be administered using art- recognized techniques. Preferably, the acetylcholinesterase inhibitor and the muscarinic agonist are administered orally, transdermally, or parenterally. In general, however, the compositions of the invention can be administered using the same art-recognized techniques used for administration of acetylcholinesterase inhibitors and muscarinic agonists. Accordingly, techniques of administration need not be repeated here.

In another aspect, the invention provides pharmaceutical compositions comprising a composition according to the invention and a pharmaceutically acceptable carrier or diluent and optionally other adjuvants. Acceptable carriers, diluents, and adjuvants are any of those commercially used in the art, in particular, those used in pharmaceutical compositions of acetylcholinesterase inhibitors and muscarinic agonists. Accordingly, such carriers, diluents, and adjuvants need not be repeated here. The following examples illustrate the present invention and will enable others skilled in the art to understand the invention more completely. EXAMPLE 1

Reversal of scopolamine-induced decreases in cognitive function in rhesus monkeys by the administration of acetylcholinesterase inhibitors and a muscarinic agonist both alone and in combination Scopolamine has been used in healthy volunteers as a model of dementia to screen for compounds for potential therapeutic usefulness in the treatment of cognitive disorders (Wesnes K, et al., Ann. NY Acad. Sci„ 1991;640:268-271). We therefore introduced scopolamine to impair the performance of rhesus monkeys on a continuous performance task. Dimunition of response was seen without a concomitant decrease in response accuracy, suggesting that scopolamine impaired the ability of these monkeys to remain attentive across time (vigilance). Similar effects have been demonstrated in both rat and human (Brown and Warburton, Psychol. Sci., 1971, 22:297-298; Parrott Psvchopharmacol. 1986;89:347-354; Wesnes K. and Warburton D.M., Neuropsvchobiology 1983,9:154-157). In monkeys, this impaired performance was shown to be mediated through blockade of central muscarinic receptors by directly infusing scopolamine into the lateral ventricle (Callahan et al., Neurobiol. Aging, 1993;14: 147-151). These changes with scopolamine are thought to result from a decrease in central cholinergic function that interferes with the efficient selection and processing of information. Scopolamine, given to healthy volunteers, has been reported to produce peripheral effects that begin to subside within 60 minutes after dosing, while cognitive performance remains impaired out to 2 hours on tasks measuring vigilance and continuous performance. To minimize peripheral effects with intramuscular dosing in monkeys, scopolamine was administered 90 minutes before testing.

The subjects were 6 adult rhesus monkeys 12+ years old, 4 females and 2 males. Continuous performance was measured using a microcomputer- controlled test environment. Briefly, test-experienced rhesus monkeys were presented a stimulus consisting of a yellow square randomly displayed on a color television monitor. Stimulus duration (1, 2, or 4 seconds) and intertrial interval (1,

2, or 3 seconds) were randomly determined in a complete block design. Animals were rewarded for responding to a target object displayed on the screen of a touch- sensitive color television monitor (CRT) by delivery of a 190 mg banana-flavored food pellet and presentation of a tone (ascending series of tones; 500 msec duration). Inaccurate responses were signaled by tone (700 Hz, 500 msec) but were not rewarded. Display of the target object on the CRT was randomized with respect to time and spatial location. Test sessions consisted of 150 trials. Responses were expressed as means + standard error of the mean. Differences between the means were analyzed using t-test for paired observations and were considered significant at a level of p <0.05. Scopolamine (0.003 or 0.006 mg/kg) was injected intramuscularly (IM)

90 minutes before testing. In these studies, 3 of the 6 monkeys were unimpaired by 0.003 mg/kg and required 0.006 mg/kg of scopolamine for testing. In the first set of experiments, l,2,3,4-tetrahydro-5-aminoacridine (0.03, 0.10, 0.32, and 1.0 mg/kg), 1 -benzyl -4-(5,6-dimethoxy-l-indanon)-2-yl)methylpiperidine (0.03, 0.10, 0.32, and 1.0 mg/kg), l,2,5,6-tetrahydro-l-methyl-3-pyridine- carboxaldehyde-O-methyloxime (0.001, 0.003, and 0.010 mg/kg), or a combination of l,2,3,4-tetrahydro-5-aminoacridine and 1,2,5,6-tetrahydro- l-methyl-3-pyridinecarboxaldehyde-O-methyloxime or 1 -benzyl - 4-(5,6-dimethoxy-l-indanon)-2-yl)methylpiperidine, and 1 ,2,5,6-tetrahydro- l-methyl-3-pyridine-carboxaldehyde-O-methyloxime were given IM 30 minutes before testing and 60 minutes after an impairing dose of scopolamine. All compounds were dissolved in 0.9% saline for injection and all doses refer to free base.

Scopolamine significantly decreased the number of correct responses made by these monkeys. Figures 1 and 2 show that this impaired performance produced by scopolamine was significantly reversed by 0.32 mg/kg of 1,2,3,4-tetrahydro- 5-aminoacridine (Figure 1) or by 0.10 mg/kg of l-benzyl-4-(5,6-dimethoxy- l-indanon)-2-yl)methylpiperidine (Figure 2) when either compound was administered 60 minutes after scopolamine and 30 minutes before testing. Figure 3 shows that CI-979, l,2,5,6-tetrahydro-l-methyl-3-pyridine- carboxaldehyde-O-methyloxime similarly produced an improvement in performance that was statistically significant only when using the best dose effect of CI-979 for each monkey, to account for individual variability. This best dose of CI-979 (0.003 or 0.010 mg/kg) in each monkey correlated with the maximum- tolerated dose free of side effects. Figures 4 and 5 show that combined treatment with l,2,3,4-tetrahydro-5-aminoacridine (0.1 and 0.32 mg/kg) and CI-979 (0.001 and 0.003 mg/kg) (Figure 4) or with l-benzyl-4-(5,6-dimethoxy- l-indanon)-2-yl)methylpiperidine (0.03 and 0.10 mg/kg) and CI-979 (0.001 and 0.003 mg/kg) (Figure 5) significantly improved performance at each of the dose combinations tested. Furthermore, at low doses l,2,3,4-tetrahydro-5- aminoacridine (0.1 mg/kg) and CI-979 (0.001 and 0.003 mg/kg), or 1-benzyl- 4-(5,6-dimethoxy- 1 -indanon)-2-yl)methylpiperidine (0.032 mg/kg) and CI-979

(0.001 mg/kg), given in combination reversed the scopolamine-induced impairment to a greater extent than did equivalent doses of either compound alone.

These effects are similar to those reported in mice, where a potentiation of cognitive function by various combinations of the cholinergics arecoline, edrophonium and oxotremorine was observed (Flood, et al., Neurobiol. Aging, 1983;4:37-43). These results in mice were obtained after direct injection of the combinations into the brain, thus minimizing the impact of potential peripheral nervous system side effects. In contrast, the instant invention utilizes intramuscular injections, which may activate both central and peripheral nervous system side effects.

EXAMPLE 2 Administration of acetylcholinesterase inhibitors and a muscarinic agonist both alone and in combination to rhesus monkeys in the absence of scopolamine In the second set of experiments, l,2,3,4-tetrahydro-5-aminoacridine (0.10,

0.32, and 1.0 mg/kg), l-benzyl-4-(5,6-dimethoxy-l-indanon)-2-yl)methyl- piperidine (0.03, 0.10, and 0.32 mg/kg) and CI-979 (0.001, 0.003, and 0.010 mg/kg), or a combination of l,2,3,4-tetrahydro-5-aminoacridine and CI-979 or l-benzyl-4-(5,6-dimethoxy-l-indanon)-2-yl)methylpiperidine and CI-979 were given IM 30 minutes before testing, in the absence of scopolamine. All compounds were dissolved in 0.9% saline for injection and all doses refer to free base. Figures 6 and 7 show that l,2,3,4-tetrahydro-5-aminoacridine (1.0 mg/kg) (Figure 6) or l-benzyl-4-(5,6-dimethoxy-l-indanon)-2-yl)methylpiperidine (0.32 mg/kg) (Figure 7) given alone 30 minutes before testing significantly decreased responses. In both cases, the impaired behavioral performance was observed in the absence of any observable side effects. Figure 8 shows that CI-979 given alone similarly produced a decrease in responses in 3 of 6 monkeys at 0.010 mg/kg that was not statistically significant. Excessive peripheral cholinergic stimulation (salivation, emesis) was observed in 2 of these monkeys. Figure 9 shows that combined treatment with l,2,3,4-tetrahydro-5-aminoacridine (0.32 mg/kg) and CI-979 (0.001 and 0.003 mg/kg), in the absence of scopolamine, did not produce adverse events significantly different from those seen with either compound alone, and no obvious peripheral side effects were observed. Figure 10 similarly shows that combined treatment with l-benzyl-4-(5,6- dimethoxy-l-indanon)-2-yl)methylpiperidine (0.03 and 0.10 mg/kg) and CI-979 (0.001 and 0.003 mg/kg) in the absence of scopolamine produced no obvious peripheral side effects or significant changes in the number of responses.

Thus, in neither case did the combination treatment potentiate the adverse effects of the individual compounds. Further, the combinations did not produce any adverse effects at the combination doses tested, which significantly reversed scopolamine-induced behavioral impairments, but were below the doses at which either compound produced side effects when given alone.

In each of these treatments the decrease in responding occurred across all stimulus durations. Sedation or motor impairments produce a selective decrease at short relative to long stimulus durations. This did not occur in the present study, suggesting that the disruptive effects observed were not due to general cognitive dulling but were probably due to peripheral side effects.

It is to be understood that the invention is not to be limited to the exact details of operation, or to the exact compounds, compositions, methods, procedures, or embodiments shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the full scope of the appended claims.

Claims

CLAIMSWhat is claimed is:

1. A composition comprising an effective amount of an acetylcholinesterase inhibitor in combination with an effective amount of a muscarinic agonist.

2. A combination of Claim 1 wherein the acetylcholinesterase inhibitor is tacrine, donepezil, exelon, metrifonate, or galantamine.

3. A combination of Claim 2 wherein the muscarinic agonist is milameline, xanomeline, 1 -aza-bicyclo [2.2.1 ]heptan-3 -one-O-[3 -(3 -methoxy- phenyl)-prop-2-ynyl]-oxime, talsaclidine, YM-796, or memric.

4. A composition of matter comprising the combination of 1 ,2,3 ,4-tetrahydro-

5-aminoacridine and l,2,5,6-tetrahydro-l-methyl-3-pyridine- carboxaldehyde-O-methyloxime .

5. A composition of matter comprising the combination of 1 -benzyl - 4-(5,6-dimethoxy- 1 -indanon)-2-yl)methylpiperidine and l,2,5,6-tetrahydro-l-methyl-3-pyridinecarboxaldehyde-O-methyloxime

6. The composition of Claim 4 wherein the ratio of said 1 ,2,3,4-tetrahydro- 5-aminoacridine relative to said l,2,5,6-tetrahydro-l-methyl-3-pyridine- carboxaldehyde-O-methyloxime is between 0.5:1 and 1000:1 by weight.

7. The composition of Claim 4 wherein the ratio of said 1 ,2,3 ,4-tetrahydro- 5-aminoacridine relative to said l,2,5,6-tetrahydro-l-methyl-3-pyridine- carboxaldehyde-O-methyloxime is between 1 :1 and 500:1 by weight.

8. The composition of Claim 4 wherein the ratio of said 1 ,2,3,4-tetrahydro- 5-aminoacridine relative to said l,2,5,6-tetrahydro-l-methyl-3-pyridine- carboxaldehyde-O-methyloxime is between 3:1 and 350:1 by weight.

9. The composition of Claim 5, wherein the ratio of said 1-benzyl-

4-(5,6-dimethoxy-l-indanon)-2-yl)methylpiperidine relative to said

1 ,2,5,6-tetrahydro-l -methyl-3-pyridinecarboxaldehyde-O-methyloxime is between 0.5:1 and 1000:1 by weight.

10. The composition of Claim 5, wherein the ratio of said 1-benzyl-

4-(5,6-dimethoxy-l-indanon)-2-yl)methylpiperidine relative to said

1 ,2,5,6-tetrahydro- 1 -methyl-3-pyridinecarboxaldehyde-O-methyloxime is between 1 :1 and 500:1 by weight.

11. The composition of Claim 5, wherein the ratio of said 1 -benzyl - 4-(5 ,6-dimethoxy- 1 -indanon)-2-yl)methylpiperidine relative to said l,2,5,6-tetrahydro-l-methyl-3-pyridinecarboxaldehyde-O-methyloxime is between 3:1 and 350:1 by weight.

12. A pharmaceutical composition comprising a composition according to Claim 1 and pharmaceutically acceptable carrier.

13. A pharmaceutical composition comprising a composition according to

Claim 2 and pharmaceutically acceptable carrier.

14. A pharmaceutical composition comprising a composition according to Claim 3 and pharmaceutically acceptable carrier.

15. A pharmaceutical composition comprising a composition according to Claim 4 and pharmaceutically acceptable carrier.

16. A pharmaceutical composition comprising a composition according to Claim 5 and pharmaceutically acceptable carrier.

17. A pharmaceutical composition comprising a composition according to Claim 6 and pharmaceutically acceptable carrier.

18. A pharmaceutical composition comprising a composition according to Claim 7 and pharmaceutically acceptable carrier.

19. A pharmaceutical composition comprising a composition according to Claim 8 and pharmaceutically acceptable carrier.

20. A method of treating central and peripheral nervous system disorders involving cholinergic hypofunction in a mammal, said method comprising administering to said mammal a cholinergic deficit state-reducing amount of at least one acetylcholinesterase inhibitor and at least one muscarinic agonist.

21. The method of Claim 20 wherein the ratio of said acetylcholinesterase inhibitor relative to said muscarinic agonist is between 0.5:1 and 1000:1 by weight.

22. The method of Claim 20 wherein the ratio of said acetylcholinesterase inhibitor relative to said muscarinic agonist is between 1 : 1 and 500: 1 by weight.

23. The method of Claim 20 wherein the ratio of said acetylcholinesterase inhibitor relative to said muscarinic agonist is between 3:1 and 350:1 by weight.

24. A method of treating central and peripheral nervous system disorders involving cholinergic hypofunction in a mammal, said method comprising administering to said mammal a cholinergic deficit state-reducing amount of a pharmaceutical composition according to Claim 12.

25. A method of treating central and peripheral nervous system disorders involving cholinergic hypofunction in a mammal, said method comprising administering to said mammal a cholinergic deficit state-reducing amount of a pharmaceutical composition according to Claim 13.

26. A method of treating central and peripheral nervous system disorders involving cholinergic hypofunction in a mammal, said method comprising administering to said mammal a cholinergic deficit state-reducing amount of a pharmaceutical composition according to Claim 14.

27. A method of treating central and peripheral nervous system disorders involving cholinergic hypofunction in a mammal, said method comprising administering to said mammal a cholinergic deficit state-reducing amount of a pharmaceutical composition according to Claim 15.

28. A method of treating central and peripheral nervous system disorders involving cholinergic hypofunction in a mammal, said method comprising administering to said mammal a cholinergic deficit state-reducing amount of a pharmaceutical composition according to Claim 16.

29. A method of treating central and peripheral nervous system disorders involving cholinergic hypofunction in a mammal, said method comprising administering to said mammal a cholinergic deficit state-reducing amount of a pharmaceutical composition according to Claim 17.

30. A method of treating central and peripheral nervous system disorders involving cholinergic hypofunction in a mammal, said method comprising administering to said mammal a cholinergic deficit state-reducing amount of a pharmaceutical composition according to Claim 18.

31. A method of treating central and peripheral nervous system disorders involving cholinergic hypofunction in a mammal, said method comprising administering to said mammal a cholinergic deficit state-reducing amount of a pharmaceutical composition according to Claim 19.

32. The method of Claim 24 wherein said central and peripheral nervous system disorder is Alzheimer's disease.

33. The method of Claim 25, wherein said central and peripheral nervous system disorder is Alzheimer's disease.

34. The method of Claim 26, wherein said central and peripheral nervous system disorder is Alzheimer's disease.

35. The method of Claim 27, wherein said central and peripheral nervous system disorder is Alzheimer's disease.

36. The method of Claim 28, wherein said central and peripheral nervous system disorder is Alzheimer's disease.

37. The method of Claim 29, wherein said central and peripheral nervous system disorder is Alzheimer's disease.

38. The method of Claim 30, wherein said central and peripheral nervous system disorder is a Alzheimer's disease.

39. The method of Claim 31 , wherein said central and peripheral nervous system disorder is Alzheimer's disease.