M1 Agonist Research Articles

Development of CDD‐0102 as a selective M1 agonist for the treatment of Alzheimer's disease

AbstractSelective muscarinic agonists might be useful in the treatment of Alzheimer's disease. To help characterize the activity and functional selectivity of two M1 muscarinic agonists, secretion of amyloid precursor protein, brain penetration, side effect profiles, cognition‐enhancing properties, oral bioavailability, and acute toxicity were evaluated. CDD‐0102 stimulated the secretion of APP from CHO‐K1 cells expressing M1 receptors and penetrated into the brain following i.p. administration in rodents. CDD‐0102 produced relatively few cholinergic side effects (e.g., diarrhea, salivation) following i.p. administration in mice. The effects of muscarinic agonists on memory function were examined following bilateral injections of 192 IgG‐saporin into the diagonal band of rats to lesion basal forebrain cholinergic pathways. 192 IgG‐saporin produced decreases in cortical and hippocampal choline acetyltransferase activity and impaired performance of a paired‐run, delayed‐alternation task in a T‐maze relative to vehicle‐injected controls. Toxin‐treated rats performed significantly better following i.p. injections (1 mg/kg) of either xanomeline or CDD‐0102 as compared with saline. Prominent cholinergic side effects (e.g., diarrhea) were apparent only following xanomeline treatments. In separate studies, oral administration of CDD‐0102 (10 mg/kg) reversed the memory deficits induced by 192 IgG‐saporin in the T‐maze task. Rats achieved 54 ± 4.2% correct choices with saline, but 94 ± 1.2% following CDD‐0102 injection. In acute toxicity studies in mice, the LD50 of CDD‐0102 was greater than 1,000 mg/kg orally; 190 mg/kg i.p. The LD50 of xanomeline was 100 mg/kg p.o. and 75 mg/kg i.p. In summary, both xanomeline and CDD‐0102 displayed beneficial effects on memory function, while CDD‐0102 also exhibited a low side effect profile and low toxicity. CDD‐0102 warrants further evaluation as a therapeutic agent for the treatment of Alzheimer's disease. Drug Dev. Res. 57:200–213, 2002. © 2003 Wiley‐Liss, Inc.

The utility of muscarinic agonists in the treatment of Alzheimer's disease.

Alzheimer's disease is a progressive neurological disorder characterized by amyloid plaques and neurofibrillary tangles along with memory and cognitive deficits associated with a loss of basal forebrain cholinergic neurons. Efforts to treat Alzheimer's disease have focused on compounds that elevate cholinergic activity such as cholinesterase inhibitors and direct acting muscarinic and nicotinic agonists. Low efficacy and poor selectivity of available compounds have limited the clinical utility of muscarinic agonists. Recent studies suggesting a role for muscarinic agonists in regulating the production of A beta raise the possibility that selective M1 agonists could be useful in treating not only the symptoms, but also the underlying cause(s) of Alzheimer's disease. Thus, renewed efforts have focused on the development of compounds with improved selectivity for M1 receptors and lower toxicity. 5-(3-ethyl-1,2,4-oxadiazol-5-yl)-1,4,5,6-tetrahydropyrimidine (CDD-0102) is a potent M1 agonist with a low side effect profile that enhances memory function in animal models of Alzheimer's disease. The available preclinical data suggest that CDD-0102 may be useful in the treatment of Alzheimer's disease.

AF150(S) and AF267B: M1 muscarinic agonists as innovative therapies for Alzheimer's disease.

The M1 muscarinic agonists AF102B (Cevimeline, EVOXACTM: prescribed in USA and Japan for Sjogren's Syndrome), AF150(S) and AF267B--1) are neurotrophic and synergistic with neurotrophins such as nerve growth factor and epidermal growth factor; 2) elevate the non-amyloidogenic amyloid precursor protein (alpha-APPs) in vitro and decrease beta-amyloid (A beta) levels in vitro and in vivo; and 3) inhibit A beta- and oxidative-stress-induced cell death and apoptosis in PC12 cells transfected with the M1 muscarinic receptor. These effects can be combined with the beneficial effects of these compounds on some other major hallmarks of Alzheimer's disease (AD) (e.g. tau hyperphosphorylation and paired helical filaments [PHF]; and loss of cholinergic function conducive to cognitive impairments.) These drugs restored cognitive impairments in several animal models for AD, mimicking different aspects of AD, with a high safety margin (e.g. AF150[S] >1500 and AF267B >4500). Notably, these compounds show a high bioavailability and a remarkable preference for the brain vs. plasma following p.o. administration. In mice with small hippocampi, unlike rivastigmine and nicotine, AF150(S) and AF267B restored cognitive impairments also on escape latency in a Morris water maze paradigm in reversal learning. Furthermore, in aged and cognitively impaired microcebes (a natural animal model that mimics AD pathology and cognitive impairments), prolonged treatment with AF150(S) restored cognitive and behavioral impairments and decreased tau hyperphosphorylation, PHF and astrogliosis. Our M1 agonists, alone or in polypharmacy, may present a unique therapy in AD due to their beneficial effects on major hallmarks of AD.

M1 and M4 muscarinic receptors from hippocampus are positively involved in memory consolidation

The muscarinic antagonist scopolamine causes amnesia in rats, both systemically or administered into the hippocampus after training, supporting the involvement of muscarinic receptors (MAChR) in memory. The role of MAChR subtypes was poorly understood in vivo due to the lack of enough selective pharmacological tools. Central M1, M3 and M5 receptors are mainly coupled to the phosphoinositide pathway, while central M2 and M4 receptors couple to the inhibition of stimulated adenylate cyclase (AC).Muscarinic toxins (MTs) from Dendroaspis snakes venom are selective for MAChR subtypes. MT1 and MT2, with affinity order M1M4 other subtypes, behaved as M1 agonists in various preparations. MT3 is highly selective for M4 receptors. These MTs fully antagonised the muscarinic inhibition of FSK‐stimulated hippocampal AC. As these MTs have negligible binding to M2 receptor, the M4 subtype must be responsible for most of the AC inhibition. Pirenzepine, an antagonist with similar affinity for M1 and M4, given into the hippocampus after an inhibitory avoidance task was amnesic. MT1 and MT2 facilitated memory consolidation, corroborating the positive involvement of M1 receptors. At a higher dose of MT2, the facilitation disappeared, suggesting that it was acting at another site, likely blocking M4 receptors. These results strongly support that M4 receptor of the hippocampus, responsible for muscarinic inhibition of AC, positively modulates memory consolidation.

Cortico‐hippocampal APP and NGF levels are dynamically altered by cholinergic muscarinic antagonist or M1 agonist treatment in normal mice

To determine whether altered cholinergic neurotransmission can modify the long-term secretion of amyloid precursor protein (APP), endogenous levels of APP and nerve growth factor (NGF), we administered a selective M1 muscarinic receptor agonist (RS86) or the muscarinic antagonist, atropine, for 7 days in vivo into young adult mice (C57BL/6j). The levels of NGF and total APP in the hippocampus, frontal cortex, striatum, parietal cortex and cerebrospinal fluid (CSF) were examined by ELISA and Western blot. We found that this repeated i.m. administration of M1 receptor agonist resulted in decreased total APP levels in the hippocampus, frontal cortex and parietal cortex, and increased secreted alpha-APPs levels in the CSF. M1 agonist treatment also resulted in decreased NGF levels in the hippocampus and CSF. These effects of the M1 muscarinic agonist could be blocked by atropine, which by itself elevated tissue levels of total APP. Interestingly, we found that the decrease of total APP in the hippocampus and striatum after M1 agonist treatment inversely correlated with the change in NGF levels. These data suggest that a sustained increased cholinergic, M1-mediated neurotransmission will enhance secretion of alpha-APPs in CSF and adaptively reduce the levels of total APP and NGF in the corticohippocampal regions of normal mice. The dynamic and adaptive regulation linking total APP and NGF levels in normal adult mice is relevant for understanding the pathophysiology of conditions with cholinergic and APP related pathologies, like Alzheimer's disease and Down's syndrome.

Impact of muscarinic agonists for successful therapy of Alzheimer's disease.

The M1 muscarinic agonists AF102B, AF150(S) & AF267B--i) restored cognitive impairments in several animal models for AD with an excellent safety margin; ii) elevated alpha-APPs levels; iii) attenuated vicious cycles induced by A beta, and inhibited A beta- and oxidative stress-induced apoptosis; and iv) decreased tau hyperphosphorylation. AF150(S) and AF267B were more effectve than rivastigmine and nicotine in restoring memory impairments in mice with small hippocampi. In apolipoprotein E-knockout mice, AF150(S) restored cognitive impairments and cholinergic hypofunction and decreased tau hyperphosphorylation. In aged microcebes, AF150(S) restored cognitive and behavioral impairments and decreased tau hyperphosphorylation, paired helical filaments and astrogliosis. In rabbits, AF267B & AF150(S) decreased CSF A beta(1-42 & 1-40), while AF102B reduced A beta(1-40). Finally AF102B decreased CSF A beta(total) in AD patients. Taken together, M1 agonists may represent a unique therapy in AD due to their beneficial effects on three major hallmarks of AD--cholinergic hypofunction, A beta and tau protein hyperphosphorylation.

Muscarinic receptors of the neostriatum--their role in controlling operant behavior in dogs.

Chronic experiments were performed on six dogs to study the effects of bilateral microinjections of muscarinic receptor agonists and blockers into the dorsal striatum on the performance of an operant defensive reflex consisting of maintenance of a specified posture and on the differentiation of stimuli. Microinjections of carbachol, a non-selective agonist of muscarinic receptors, were accompanied by increases in the tonic component of movements, inhibition of phasic movements, ordering of the postural rearrangement, and increases in the amplitudes of its components. Bilateral microinjections of the selective agonist oxotremorine into the neostriatum had significantly weaker effects on the amplitude of postural rearrangement, generally decreasing the amplitude. Although oxotremorine also increased the tonic component of the operant response, this effect was weaker than that seen with carbachol microinjections. In addition, oxotremorine, unlike carbachol increased the number of intersignal limb elevations. These data, along with data published in the literature, are used to suggest the hypothesis that the actions of oxotremorine are mediated not only via muscarinic M2 but also via M1 receptors in the neostriatum. Stronger changes in responses to differential stimuli were also obtained after microinjection of the non-selective agonist carbachol than after microinjection of oxotremorine, and the fact that changes in responses to differential stimuli were significantly greater than changes in those to defensive stimuli suggests that microinjections of muscarinic M1 and M4 receptor agonists into the striatum are also accompanied by improvements in attention to significant stimuli.

Chemical genomics: massively parallel technologies for rapid lead identification and target validation.

Chemical genomics is a new research paradigm with importantapplications in drug discovery. It links genomic targets withsmall-molecule chemistries thereby allowing for efficient targetvalidation and lead compound identification. ACADIA'schemical-genomics platform consists of a large and diverse small-moleculelibrary (800,000), a reference drug library (2,000), druggablegenomic targets (>300) and a cell-based functional assaytechnology (R-SAT(TM); Receptor Selection and AmplificationTechnology) that allows for ultra-high throughput screening(>500,000 data points/week) as well as high throughputpharmacology and profiling over a wide range of targets. Twoexamples are presented that illustrate the success of ourchemical-genomics approach: (i) The validation of inverse agonismat serotonin 5-HT(2A) receptors as an antipsychotic mechanismand the subsequent discovery of potent and selectively acting 5-HT(2A) inverse agonists, currently in preclinical development,and (ii) the discovery of the first ectopically binding subtype-selective muscarinic m1 agonist.

Infralimbic muscarinic M1 receptors modulate anxiety-like behaviour and spontaneous working memory in mice

Spontaneous working memory and anxiety-like behaviour can be concurrently influenced following kappa 1 opioid agonist or antagonist infusions in the infralimbic (IL) area of the ventromedial prefrontal cortex (vmPFC) in CD-1 mice. The present study sought to evaluate whether acetylcholine (ACh) muscarinic (M) receptor drugs can similarly influence these cognitive-behavioural processes in the IL cortex. Anxiety was evaluated in the elevated plusmaze and spontaneous working memory was evaluated in the Y-maze following scopolamine, pirenzepine or McN-A-343 infusion in the IL cortex. In experiment 1, the non-specific muscarinic receptor antagonist, scopolamine, was anxiogenic in trial 1 (5, 10 and 20 nmol), but did not influence behaviour in trial 2 (no-injection) in the elevated plus-maze 24 h later. In week 2, scopolamine disrupted spontaneous working memory in the Y-maze at the highest dose (20 nmol). In experiment 2, pretreatment with the M1 antagonist, pirenzepine, was anxiolytic in trial 1 (5 and 10 nmol), as well as in trial 2 (no-injection) in the elevated plus-maze 24 h later (0.25, 1.25, 2.5, 5 and 10 nmol). In week 2, pirenzepine disrupted spontaneous working memory in the Y-maze (2.5, 5 and 10 nmol). In experiment 3, pretreatment with the M1 agonist, McN-A-343, was anxiogenic in trial 1 (2.5, 5, 10 and 20 nmol), as well as in trial 2 (no-injection) in the elevated plus-maze 24 h later (2.5, 5, 10 and 20 nmol). In week 2, McN-A-343 enhanced spontaneous working memory in the Y-maze (2.5, 5, 10 and 20 nmol). (1) Enhanced ACh transmission in the vmPFC induces anxiety in challenging environments and enhances spontaneous working memory performance. (2) Blocking or activating postsynaptic M1 receptors in the vmPFC may truncate or exaggerate, respectively, afferent anxiety-relevant information. (3) IL pirenzepine and McN-A-343 exert long-term opposite effects on aversive learning during trial 1 in the elevated plus-maze.

M1 muscarinic agonists as potential disease-modifying agents in Alzheimer's disease. Rationale and perspectives.

A cholinergic hypofunction in Alzheimer's disease (AD) may lead to formation of beta-amyloids that might impair the coupling of M1 muscarinic ACh receptors (mAChRs) with G proteins. This disruption in coupling can lead to decreased signal transduction, to a reduction in levels of trophic amyloid precursor proteins (APPs), and to generation of more beta-amyloids that can also suppress ACh synthesis and release, aggravating further the cholinergic deficiency. These "vicious cycles," a presynaptic and a postsynaptic one, may be inhibited, in principle, by M1 selective agonists. Such properties can be detected in the functionally selective M1 agonists from the AF series [e.g., project drugs, AF102B, AF150(S)]. These M1 agonists promote the nonamyloidogenic APP processing pathways and decrease tau protein phosphorylation. The effects on tau proteins suggest a link between M1 mAChR-mediated signal transduction system(s) and the neuronal cytoskeleton via regulation of phosphorylation of tau microtubule-associated protein. This may indicate a dual role for M1 agonists: as inhibitors of two "vicious cycles," one induced by beta-amyloids, and the other due to overactivation of certain kinases (e.g., glycogen synthase kinase-3, GSK-3) or downregulation of phosphatases, respectively. Prolonged administration of AF150(S) in apolipoprotein E-knockout mice restored cognitive impairments, cholinergic hypofunction, and tau hyperphosphorylation, and unveiled a high-affinity binding site to M1 mAChRs. Except M1 agonists, there are no reports of compounds having such combined effects, for example, amelioration of cognition dysfunction and beneficial modulation of APPs together with tau phosphorylation. This unique property of M1 agonists to alter different aspects of AD pathogenesis could represent the most remarkable, yet unexplored, clinical value of such compounds.

The selective muscarinic M1 agonist AF102B decreases levels of total A? in cerebrospinal fluid of patients with Alzheimer's disease

beta-Amyloid (Abeta) deposits in diffuse and compact senile plaques in the brain are one of the defining histopathological features of Alzheimer's disease (AD). Preventing Abeta deposition is a goal of drug therapy for AD, because excessive amounts of Abeta may be toxic to neurons. In preclinical studies, activation of the muscarinic M1 receptor subtype inhibited Abeta secretion from cultured cells. To determine whether a similar sequence occurs in human beings, we administered the selective M1 agonist AF102B to 19 AD patients and measured total Abeta (Abeta(total)) levels in cerebrospinal fluid (CSF) before and during treatment. Abeta(total) levels in CSF decreased in 14 patients by 22%, increased in 3 patients, and were unchanged in 2 patients; the overall decrease in the group as a whole was statistically significant. To test the specificity of the M1 effect, we also measured the relative changes in Abeta(total) levels in CSF during treatments in separate sets of AD patients with the acetylcholinesterase inhibitor physostigmine or the anti-inflammatory drug hydroxychloroquine. CSF Abeta(total) levels did not change significantly in the 9 AD patients in the physostigmine protocol or in the 10 AD patients in the hydroxychloroquine study. These data provide evidence that the activation of M1 receptors reduces Abeta levels in the CSF of AD patients. If this effect also occurs in brain, M1 agonists may have long-term therapeutic benefits by lowering amyloid in AD.

The selective muscarinic M1 agonist AF102B decreases levels of total Aβ in cerebrospinal fluid of patients with Alzheimer's disease

The selective muscarinic M1 agonist AF102B decreases levels of total Aβ in cerebrospinal fluid of patients with Alzheimer's disease

Interaction between α-MSH and acetylcholinergic system upon striatal cAMP and IP 3 levels

The interaction between the neuropeptide α-MSH and the acetylcholinergic system as reflected by changes in cAMP and inositol 1–3-5 triphosphate(IP 3)production was investigated in an in vitro model of striatal slices. The possible involvement of D 1 receptors in cholinergic and α-MSH- stimulated cAMP and IP 3 production in slices of rat striatum was also examined, because it has been demonstrated that acetylcholinergic drugs induce endogenous dopamine release in the striatum. α-MSH, pilocarpine(PL) and the selective muscarinic M1 agonist McN-A-343 increased cAMP and IP 3 striatal levels, effects blocked by the D 1 antagonist SCH-23390, except for the effects of α-MSH on IP 3 .The muscarinic M 2 antagonist gallamine (GL) brought about an increase in cAMP levels, an effect blocked by SCH-23390. The M 1 antagonist pirenzepine (Pz) induced a decrease both in cAMP and IP 3 content, and the nicotinic antagonist di-hydro-β-eritroidine(DBE) only diminished cAMP production. When α-MSH and cholinergic agents were simultaneously added, cAMP and IP 3 levels were modified with respect to the values reached when these agents were added alone. An interaction between the acetylcholinergic system and α-MSH through M 1 and nicotinic receptors was also observed. These results suggest that the intracellular signaling pathways related to cAMP and IP 3 production gated by α-MSH and these cholinergic receptors are probably related. α-MSH striatum cAMP IP 3 muscarinic and nicotinic receptors an in vitro model.

The M1 Muscarinic Agonist CI-1017 Facilitates Trace Eyeblink Conditioning in Aging Rabbits and Increases the Excitability of CA1 Pyramidal Neurons

The M1 muscarinic agonist CI-1017 was administered intravenously to aging rabbits on a daily basis before and during hippocampally dependent trace eyeblink conditioning sessions. Circulating levels of CI-1017 were significantly related to the drug dose. The drug was found to significantly increase the rate and amount of learning in a dose-dependent manner with no significant effects on the amplitude, area, or latency of conditioned responses. There was no evidence of pseudoconditioning at the highest drug concentration, and the minimally effective dose produced only mild and temporary hypersalivation as a side effect. CI-1017 (10 microM) was also found to increase the excitability of CA1 pyramidal neurons recorded from hippocampal slices from young and aging naive rabbits as measured by changes in spike-frequency adaptation and the postburst afterhyperpolarization. These biophysical changes were reversed with either atropine (1 microM) or pirenzepine (1 microM). These results suggest that M1 agonists ameliorate age-related learning and memory impairments at least in part by reducing the afterhyperpolarization and spike-frequency adaptation of hippocampal pyramidal neurons and that M1 agonists may be an effective therapy for reducing the cognitive deficits that accompany normal aging and/or Alzheimer's disease.

M1 muscarinic agonists: Their potential in treatment and as disease-modifying agents in Alzheimer's disease

M1-type muscarinic receptors (mAChR) have an important role in cognitive processing and are relatively unchanged in Alzheimer's disease (AD). Therefore, M1 agonists represent a rational treatment strategy of AD. However, some muscarinic agonists showed disappointing results in Phase III studies in AD patients. These agonists lacked M1 selectivity in vivo and/or had several major clinical limitations, precluding a proper testing of the clinical concept. There is now justified hope that selective M1 agonists could provide limited causal therapy in AD. Thus, a relation between the formation of β-amyloid peptide and amyloid plaques, tau phosphorylation, and loss of cholinergic function in AD brains has been reported. This may shift the interest in such compounds from a mere symptomatic treatment toward their use in the future as disease-modifying agents via muscarinic regulation of β-amyloid metabolism and tau phosphorylation. Such characteristics can be detected in the functionally selective M1 agonists from the AF series (e.g. AF102B, AF150(S), AF267B). These M1 agonists, inter alia, restore cognitive impairments in several animal models for AD, promote the neurotrophic and nonamyloidogenic amyloid precursor protein (APPs) processing pathways, and decrease tau protein phosphorylation. Apolipoprotein E-deficient mice have memory deficits, synaptic loss of basal forebrain cholinergic projections, and hyperphosphorylation of distinct epitopes of the microtubule-associated protein tau. These impairments are restored by subchronic treatment with AF150(S). Furthermore, prolonged administration of AF150(S) restored cognitive and behavioral impairments in aged microcebes, an animal model that mimics AD pathology. Except M1 agonists, there are no reports on compounds having combined effects, e.g., amelioration of cognition dysfunction and beneficial modulation of APPs together with tau phosphorylation. This unique property of M1 agonists to alter different aspects associated with AD pathogenesis could represent the most remarkable, yet unexplored, or even ignored, clinical value of such drugs. Finally, EVOXAC™ (Cevimeline, AF102B) was recently approved by the FDA for the treatment of dry mouth in Sjogren syndrome, an autoimmune disease that affects exocrine glands. Drug Dev. Res. 50:291–297, 2000. © 2000 Wiley-Liss, Inc.

Therapeutic Strategies in Alzheimer’s Disease: Ml Muscarinic Agonists

The cholinergic hypofunction in Alzheimer's disease (AD) appears to be linked with two other major hallmarks of this disease, beta-amyloid and hyperphosphorylated tau protein. Formation of beta-amyloids might impair the coupling of M1 muscarinic acetylcholine receptors (mAChR) with G-proteins. This can lead to decreased signal transduction, a decrease of trophic and non-amyloidogenic amyloid precursor protein (APPs) and generation of more beta-amyloids, aggravating further the cholinergic deficiency. This review is an attempt to explore the M1 mAChR regulation of beta-amyloid metabolism, tau hyperphosphorylation and cognitive functions. The therapeutic potential of M1-selective muscarinic agonists including AF102B, AF150(S), AF267B (the AF series) is evaluated and compared, when possible, with several FDA-approved acetylcholinesterase inhibitors. These M1 agonists can elevate APPs, decrease tau protein phosphorylation/hyperphosphorylation in vitro and in vivo and restore cognitive impairments in several animal models for AD. Except for the M1 agonists, no other compounds were reported yet with combined effects; e.g., amelioration of cognition dysfunction and beneficial modulation of APPs/beta-amyloid together with tau hyperphosphorylation/phosphorylation. This property of M1 agonists to alter different aspects associated with AD pathogenesis could represent the most remarkable clinical value of such drugs.

Evaluation of blood-brain barrier passage of a muscarine M1 agonist and a series of analogous tetrahydropyridines measured by in vivo microdialysis.

To investigate the blood-brain barrier (BBB) passage of the M1 muscarine agonist Lu 25-109 (5-(2-Ethyl-2H-tetrazol-5-yl)-1,2,3,6-tetrahydro-methylpyridine) and potential metabolites using in vivo microdialysis. Anesthetized rats were administered an intravenous infusion of one of seven analogs with a Log D7.4 ranging from 0.35 to -2.4. Microdialysis probes were implanted in the brain and the jugular vein. The integrity of the BBB was evaluated using 2-amino-3-(3-hydroxy-5-phenylisoxazol-4-yl)propionic acid (APPA), a compound not expected to penetrate the BBB. The data was corrected for in vitro recovery. Lu 25-109, Lu 24-165 (demethylated Lu 25-109) and Lu 25-077 (N-demethylated Lu 25-109) entered the brain in a 1:1 ratio with the blood. Although Lu 29-081 (hydroxylated Lu 25-109) presented a similar Log D7.4 to Lu 25-109 and Lu 24-164, it entered the brain with a lower brain:blood ratio of 0.5. Lu 32-181 (Lu 25-109 N-oxide), Lu 35-026 (deethylated and oxidized Lu 25-109) and Lu 31-126 (deethylated Lu 25-109) were not detected in the brain samples, indicating no penetration. Infusion of Lu 25-109 resulted in a time perspective of the formation and distribution of the two metabolites Lu 25-077 and Lu 32-181. Although the hydroxylated compound (Lu 29-081) had a Log D74 of -0.6, within the range 0.35 to -0.83 of the compounds penetrating the BBB, it showed a brain: blood ratio of 0.5. Lu 35-026 showed an unusual infusion profile with a tmax of 100-150 min and a subsequent decrease in blood concentration. Compounds with Log D7.4 above -0.83 penetrated the BBB, whereas compounds below -1.5 did not. Knowledge of Log D7.4 values is not sufficient to evaluate BBB passage because the value does not predict the influence of active transport processes.

PACAP upsets stomach theory.

PACAP upsets stomach theory.

Divided attention-enhancing effects of AF102B and THA in aging monkeys.

The effects of cholinergic drugs proposed for treatment of cognitive impairment in normal aging and dementia on divided attention have been little studied in non-human primates. We tested the hypothesis that cholinergic drugs improve spatial divided attention in primates via a computer task requiring simultaneous tracking of two visual targets in three young and two aged healthy bonnet macaques. Task accuracy (number of correct responses) and reaction time (RT) were measured 2 h after administration of either the m1 agonist +/- -cis-2-methyl-spiro(1,3-oxathiolane-5,3')quinuclidine (AF102B; 0.1-2.1 mg/kg IM) or the cholinesterase inhibitor 9-amino-1,2,3,4-tetrahydroamino-acridine (THA; 0.5-2.0 mg/kg orally). Accuracy increased for four of five monkeys at appropriate doses of one or both cholinomimetics, accompanied in two monkeys by a drop in RT. Responses were less uniform to THA than to AF102B. For the five-monkey group at Best dose, accuracy increased 34% (THA) or 43% (AF102B) above baseline (P<0.05 for both drugs), respectively, with no significant change in RT and with minimal untoward effects. Cholinotherapy may improve divided attention in young and aged healthy primates.

Galanin inhibits performance on rodent memory tasks.

Central administration of galanin produces performance deficits on a variety of rodent learning and memory tasks. Galanin impairs acquisition and/or retention of the Morris water task, delayed nonmatching to position, T-maze delayed alternation, starburst radial maze, and passive avoidance in normal rats. A primary site of action is the ventral hippocampus, with an additional modulatory site in the medial septum-diagonal band. The behavioral actions of galanin at rat septohippocampal sites mediating cognitive processes are consistent with previous reports of inhibitory actions of galanin on acetylcholine release and cholinergically activated transduction at the M1 muscarinic receptor in rat hippocampus. The peptidergic galanin receptor antagonist M40 blocks the inhibitory actions of galanin on memory tasks. Treatment combinations of M40 with an M1 agonist, TZTP, improves performance on delayed nonmatching to position, in rats with 192IgG-saporin-induced cholinergic lesions of basal forebrain neurons. Nonpeptide, bioavailable, subtype-selective galanin receptor antagonists may provide tools to test the hypothesis that antagonism of endogenous galanin, which is overexpressed in the basal forebrain in Alzheimer's patients, can contribute to the alleviation of the cognitive deficits associated with Alzheimer's disease.