Muscarinic M1 preferring agonists may improve cognitive deficits associated with Alzheimer's disease. Side effect assessment of the M1 preferring agonist WAY-132983 showed significant salivation (10 mg/kg i.p. or p.o.) and produced dose-dependent hypothermia after i. p. or p.o. administration. WAY-132983 significantly reduced scopolamine (0.3 mg/kg i.p.)-induced hyperswimming in mice. Cognitive assessment in rats used pretrained animals in a forced choice, 1-h delayed nonmatch-to-sample radial arm maze task. WAY-132983 (0.3 mg/kg i.p) significantly reduced scopolamine (0.3 mg/kg s.c.)-induced errors. Oral WAY-132983 attenuated scopolamine-induced errors; that is, errors produced after combining scopolamine and WAY-132983 (to 3 mg/kg p.o.) were not significantly increased compared with those of vehicle-treated control animals, whereas errors after scopolamine were significantly higher than those of control animals. With the use of miniosmotic pumps, 0.03 mg/kg/day (s.c.) WAY-132983 significantly reduced AF64A (3 nmol/3 microliter/lateral ventricle)-induced errors. Verification of AF64A cholinotoxicity showed significantly lower choline acetyltransferase activity in the hippocampi of AF64A-treated animals, with no significant changes in the striatal or frontal cortex. Cognitive assessment in primates involved the use of pretrained aged animals in a visual delayed match-to-sample procedure. Oral WAY-132983 significantly increased the number of correct responses during short and long delay interval testing. These effects were also apparent 24 h after administration. WAY-132983 exhibited cognitive benefit at doses lower than those producing undesirable effects; therefore, WAY-132983 is a potential candidate for improving the cognitive status of patients with Alzheimer's disease.
Rational drug design utilizing a receptor homology model of the human muscarinic M1 receptor led to the discovery of the highly potent (Ki = 2 nM), efficacious, and in vivo functionally-selective M1 agonist, WAY-132983.
Title: Arecoline via miniosmotic pump improves AF64A-impaired radial maze performance in rats: a possible model of Alzheimer's disease Bartolomeo AC, Morris H, Boast CA Ref: Neurobiol Learn Mem, 68:333, 1997 : PubMed
Male Sprague-Dawley rats, preoperatively trained in a 1-h delay non-match-to-position radial maze task, received bilateral stereotaxic injections of a selective cholinotoxin, ethylcholine aziridinium ion (AF64A: 3 nmol/3 microliters/lateral ventricle). Animals treated with AF64A made significantly more total postdelay errors than vehicle controls. Sustained delivery, via miniosmotic pumps, of arecoline (0.1, 0.3, 1, 3, 10, or 30 mg/kg/day sc for 14 days) attenuated the AF64A-induced cognitive impairment in a dose-dependent manner, producing an inverted U-shaped dose-response function which was optimal at 1.0 mg/kg/day. Following these studies, choline acetyltransferase activity was significantly reduced in hippocampi extracted from the AF64A-treated rats, indicating successful cholinotoxicity. This paradigm may be useful as a possible screen for potential Alzheimer's disease therapeutic agents. This conclusion is supported by published reports of beneficial arecoline effects observed following 2-week intravenous infusions in patients with Alzheimer's disease (Soncrant, Raffaele, Asthana, Berardi, Morris, & Haxby, 1993).
Title: Task difficulty determines the differential memory-impairing effects of EAA antagonists in gerbils Maurer SA, Storch FE, LaForge RR, Boast CA Ref: Pharmacol Biochem Behav, 51:345, 1995 : PubMed
Excitatory amino acid antagonists (EAAAs) have been shown to disrupt learning and memory in a variety of cognitive tasks. EAAAs have been reported to produce differential effects on working memory (WM) and reference memory (RM) or to have no effect at all. Apparent selective effects of EAAAs on WM and/or RM may have been due to differences between the effects of competitive and noncompetitive EAAAs, dose selection, or to different task requirements for the WM and RM components. In the present experiments, we assessed the effects of a noncompetitive EAAA (MK-801), a competitive EAAA (CPP), and the muscarinic antagonist scopolamine in two cognitive tasks, the split-stem T-maze and the eight-arm radial maze. In these two tasks, the WM and the RM components differed in their relative degree of difficulty. Gerbils were trained on either the T-maze, where WM was more difficult than RM, or on the radial arm maze, where RM was more difficult than WM. In the T-maze, MK-801 (0.1 mg/kg, IP, 30 min prior), CPP (30.0 mg/kg, IP, 2 h prior) and scopolamine (0.3 mg/kg, IP, 30 min prior) impaired both WM and RM, but the magnitude of the impairing effect was statistically greater for the WM component, the more difficult of the two components. Lower doses of these three compounds produced either selective effects on WM or no effect at all. In the radial arm maze all three drugs impaired both components, but the magnitude of the impairing effect was statistically greater for the RM component, the more difficult of the two components.(ABSTRACT TRUNCATED AT 250 WORDS)
Selective M1 cholinergic agonists may be useful in treating dementias due to cholinergic hypofunction. SR 95639 has recently been described as such a compound. We found the compound to have affinity for M1 sites (Ki = 2.1 microM) which was approximately 3-fold higher than its affinity for M2 sites. Functional partial agonism was suggested by an inconsistent increase in phosphoinositide (PI) turnover in rat hippocampal slices, combined with blockade of carbachol-stimulated PI turnover. In vivo M2-mediated effects were absent. Scopolamine-induced hyperactivity was attenuated by SR 95639 and scopolamine-impaired inhibitory avoidance and radial maze performance were improved. The compound appears to be a weakly selective M1 partial agonist with potential advantages over existing compounds.
Title: Searching for models of Alzheimer's disease: a comparison of four amnestic treatments in two behavioral tasks Murphy DE, Boast CA Ref: Annals of the New York Academy of Sciences, 444:450, 1985 : PubMed
Recently, compounds which bind avidly to benzodiazepine binding sites have been shown to possess diazepam antagonist properties. For example, the benzodiazepine RO 15-1788 and the pyrazoloquinoline CGS 8216 can antagonize the anxiolytic, sedative, muscle relaxant and anticonvulsant properties of diazepam. The beta-carbolines have also been shown to antagonize several actions of diazepam. Other compounds including physostigmine, naloxone, bicuculline, picrotoxin, caffeine and theophylline, lack appreciable affinity for benzodiazepine binding sites but do antagonize at least some of the behavioral actions of diazepam. Their antagonist properties are probably the result of opposing pharmacological actions rather than direct receptor antagonism. Clinically, a potent safe diazepam antagonist could be used to reverse effects of diazepam overdose and to speed recovery of diazepam-treated patients after various out-patient procedures.
Title: The muscarinic stimulation of phospholipid labeling in hippocampus is independent of its cholinergic input Fisher SK, Boast CA, Agranoff BW Ref: Brain Research, 189:284, 1980 : PubMed
