Abraham Fisher

Selective muscarinic agonists that are directed at the ml muscarinic acetylcholine receptor (Ml mAChR) have been suggested as a rational treatment of Alzheimer’s disease (AD) (Fisher and Barak, 1995). Such muscarinic receptor agonists may activate a variety of transduction pathways, some of which are beneficial while others may be deleterious to AD. For example, activation of Ml mAChR increases phosphoinositide (PI) hydrolysis, arachidonic acid release, elevates intracellular calcium, increases the nonamyloidogenic processing of beta-amyloid precursor protein (APP), mediates tau dephosphorylation, induces formation of neurites and increases adenylate cyclase (AC) activity (Fisher and Barak, 1995; Haring et al., 1995; Heldman et al., 1996; Pittel et al., 1996). While most of these biochemical responses are considered to be beneficial for alleviating AD pathology, activation of AC may be deleterious, since mRNA of Gs, that mediates activation of AC, is elevated in AD brain (Harrison e...

Choline deficiency in brain function has been implicated in several neurological disorders. Therefore, the usefulness of choline and its analogues as therapeutic agents or potential tools in developing selective models of central cholinergic hypofunction has been under investigation. The inhibitory potencies of ethylcholine mustard (AF64) and ethylcholine mustard aziridium (AF64A) were tested in inhibiting specific (/sup 3/H)HC-3 (rat striatal membranes), (/sup 3/H)PZ and (/sup 3/H)(-)QNB (cortical and heart membranes). AF64 and AF64A inhibited the binding of (/sup 3/H)HC-3 with low affinity. Results for one-site fit are: AF64: IC/sub 50/ = 107 ..mu..M, n/sub H/ = 0.62; AF64A: IC/sub 50/ = 130 ..mu..M, n/sub H/ = 0.56. Two site-fit resulted IC/sub 50/ values of 11-12 ..mu..M for high affinity and 360-730 ..mu..M for low affinity (relative proportions: 45% and 55%, respectively) in both cases. AF30 (a rigid choline analogue with agonist activity), AF64 and AF64A were weak inhibitors ...

Alzheimer’s disease (AD) is characterized, inter alia, by synaptic loss, neurofibrillary tangles, amyloid plaques containing the β-amyloid peptide (Aβ), and degeneration of cholinergic neurons that ascend from the basal forebrain to cortical and hippocampal areas (reviewed by Court and Perry, 1991). A presynaptic cholinergic hypofunction, as one of the major neuronal events in AD, is reflected, inter alia, in reduced levels of acetylcholine (ACh), acetylcholinesterase (AChE) and choline acetyltransferase (ChAT). As a result of neuronal degeneration, the density of presynaptic M2 muscarinic receptors (mAChR) is significantly decreased in AD, yet post-synaptic Ml mAChR are relatively unchanged in AD (review by Court and Perry, 1991) (vide infra for further discussion). Degeneration of cholinergic neurons in AD is presumably a principal cause of the dementia. The “cholinergic hypothesis’.in AD implies that a cholinergic replacement therapy might be beneficial in alleviating some of the cognitive dysfunctions in this disorder (Court and Perry, 1991). Highly selective ml agonists, producing cellular excitation, should be beneficial in AD, regardless of the extent of degeneration of presynaptic cholinergic projections to the frontal cortex or hippocampus. This represents the most relevant approach of cholinergic treatment due to the role of Ml mAChRs in memory and learning processing (Fisher and Barak, 1994, Fisher, 1997). The present overview is an attempt to address some of these findings and to propose an unifying hypotheses regarding ml selective agonists aimed at treatment and therapy of AD.

Five human muscarinic acetylcholine receptors (mAChR) (ml–m5), have been cloned and expressed in suitable cell systems (reviewed by Hulme et al., 1990). * mAChRs have two binding domains, a ligand-binding extracellular (and including membrane-spanning) domain and a G-protein binding intracellular domain. This second domain, by interaction with various G-proteins, controls and modulates second messenger systems (Hulme et al., 1990).

Restoration of ACh levels or replacement with an M1 (or m1) muscarinic agonist may be effective in treating at least some of the cognitive symptoms in Alzheimer’s disease (AD), (see Court and Perry, 1991; Fisher and Barak, 1994). Treatment approaches for AD have to address abnormalities occurring also along various signal transduction pathways (Harrison et al., 1991). Novel activities associated with m1 muscarinic receptors (m1 mAChR) indicate that m1 agonists may also activate hypofunctional signalling pathways in AD (Fisher and Barak, 1994; Gurwitz et al., 1994).

To date five structurally different human muscarinic acetylcholine receptor (mAChR) subtypes (ml-m5) proteins have been cloned and expressed in suitable cell systems (Bonner et al., 1987). It is likely that the ml, m2, m3, and m4 AChRs fit the pharmacological definition of the M1, M2, M3 and M4 AChRs, respectively (Buckley et al., 1989; reviewed by Hulme et al., 1990). Muscarinic receptors are members of the G-protein coupled receptor superfamily. The mAChRs have two binding domains, a ligand-binding extracellular (and including membrane-spanning) domain and a G-protein binding intracellular domain. This second domain, by interaction with various G-proteins, controls and modulates second messenger systems. It was shown that the ml, m3 and m5 AChRs are closely related in sequence and apparently are functionally almost similar. When expressed in mammalian cells, these receptor subtypes couple efficiently to phosphoinositide (PI) turnover. The m2 and m4 AChRs are less related to the ml, m3 and m5 AChRs, and when expressed in mammalian cells are efficiently coupled to the inhibition of adenylate cyclase (Bonner et al., 1987; Hulme et al., 1990).

AF102B [(+-)-cis-2-methyl-spiro(1,3-oxathiolane-5,3')quinuclidine], a structurally rigid analog of acetylcholine, was investigated in a number of neurochemical, pharmacological and behavioral tests related to cholinergic functions. AF102B induced atropine-sensitive contractions of isolated guinea pig ilea and trachea preparations with EC50 values of 3.5 and 3 microM being 87- and 1.3-fold less potent than acetylcholine, respectively. Binding studies using the radioligands pirenzepine, cis-dioxolane and quinuclidinyl benzilate in rat cerebral cortex and quinuclidinyl benzilate in cerebellar homogenates indicated that AF102B was a potent and highly selective M1-type muscarinic probe, being more selective for M1 receptors than oxotremorine, carbachol and AF102A (the trans-isomer of AF102B). AF102B had a 3-fold higher apparent affinity for M1 receptors than the prototype M1 agonist, McN-A-343, cis- and trans-AF30 (other rigid analogs of acetylcholine). Treatment of rat cortical homo...

Background. An important step in the analysis of positron emission tomography (PET) studies of the brain is the definition of regions of interest (ROI). Image coregistration, ROI analysis, and quantification of brain PET data in small animals can be observer dependent. The purpose of this study was to investigate the feasibility of ROI analysis based on a standard MR template and an additional [18F]NaF scan.Methods. [18F]NaF scans of 10 Wistar rats were coregistered with a standard MR template by 3 observers and derived transformation matrices were applied to corresponding [11C]AF150(S) images. Uptake measures were derived for several brain regions delineated using the MR template. Overall agreement between the 3 observers was assessed by interclass correlation coefficients (ICC) of uptake data. In addition, [11C]AF150(S) ROI data were compared withex vivobiodistribution data.Results. For all brain regions, ICC analysis showed excellent agreement between observers. Reproducibility, ...

The postulated involvement of the cholinergic system in Alzheimer’s disease (AD) has highlighted the research and therapeutic approach of this affliction during the last decade (1). There is little doubt at the present stage that a clear hypofunction of the cholinergic system is in evidence in certain brain areas in AD patients. Other neurotransmitter systems seem to be relatively unaffected (1).

Amyloid β peptide (Aβ) accumulation in distinct brain regions is an early event in the progression of Alzheimer’s disease (AD). Increase in specific isoforms of Aβ production and/or aggregation appears concomitantly with several mutations. These include: 1) β-amyloid precursor protein (βAPP) mutations (Citron et al., 1992; Haass et al., 1994); 2) apolipoprotein E4 (apoE4) polymorphism (Corder et al., 1993); 3) presenilin 1 mutations (Scheuner et al., 1996); and 4) presenilin 2 mutations (Scheuner et al., 1996). The increased levels of Aβ may cause neurotoxicity and consequently lead to an inflammatory process which results in formation of extracellular plaques. The precursor of Aβ, β-amyloid precursor protein (βAPP), may be cleaved by the proteolytic enzymes β and y secretase to yield amyloidogenic products or by x03B1;-secretase which cleaves βAPP within the βA sequence and thereby prevents Aβ formation. The result of α-secretase cleavage is the release of soluble βAPP (βAPPs) to the extracellular milieu, the non-amyloidogenic products. βAPPs is constitutively secreted in the brain into extracellular fluids like the cerebrospinal fluid (CSF). The synthesis and processing of βAPP was shown to be regulated by several neurotransmitters. Acetylcholine (ACh), which is significantly decreased in AD may mediate βAPP processing via muscarinic acetylcholine receptors (mAChR). In this regard, ml mAChR mediate βAPPs processing (Nitsch et. al., 1992 & Pittel et al., 1996). Noradrenaline and serotonin were also shown to affect βAPPs secretion (Wallace & Haroutunian, 1993). In this study we tested the involvement of ACh in regulating βAPPs secretion in vivo, ex vivo and in primary cell cultures.

Alzheimer’s Disease or Senile Dementia of Alzheimer’s Type (SDAT) is characterized clinically by a progressive chronic cognitive impairment; severe for memory of recent events, whereas memory for the past remains relatively intact (1). Histopathological studies on brains of SDAT patients revealed characteristic abnormalities such as senile plaques, neurofibrillary tangles and granulovacuolar degeneration in select brain areas (2–5).

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Alzheimer’s disease (AD) is a progressive, neurodegenerative disease characterized, inter alia, by memory and cognitive loss, synaptic loss, amyloid plaques containing the β-amyloid (Aβ) peptide, degeneration of cholinergic neurons that ascend from the basal forebrain to cortical and hippocampal areas, and neurofibrillary tangles (NFT) (review: Blennow, deLeon, & Zetterberg, 2002).

The present work is an attempt to elucidate: (1) whether highly rigid structural analogs of acetylcholine are still capable of activating the muscarinic receptor; (2) whether such analogs, be they agonists or antagonists, discriminate among the various ACh-mediated functions, thereby providing a tool for the study of a possible receptor heterogeneity; (3) whether structural rigidity is a significant factor in the kinetics of drug-receptor interaction. To this end, we investigated some properties of drugs in the spiro-(1,3-dioxolane-4,3')-quinuclidine system (SDQ) which embodies the muscarinic pharmacophore in a framework of utmost rigidity. Wherever possible, these properties were compared with those of a closely related but more flexible analog. Variation in effect between members of a rigid-flexible pair or among drugs of varying rigidity is considered to reflect varying affinities towards various sites of action. 2-Methyl-spiro-(1,3-dioxolane-4,3')-quinuclidine (AF-30) is a weak but selective muscarinic agonist. It can be viewed as a highly rigid version of 3-acetoxyquinuclidine (3-AcQ) and it can be used as a probe for detection of heterogeneity among muscarinic receptors. AF-30 is equipotent with 3-AcQ in causing tremors (mice), but has 1/17th the activity of 3-AcQ in the guinea-pig ileum, 1/30th in lowering blood pressure (cats) and 1/10th in inducing analgesia (mice). 2-Diphenylmethyl-spiro(1,3-dioxolane-4',3)-quinuclidine (AF-41) and 2.2-diphenyl-spiro-(1,3-dioxolane-4,3')-quinuclidine (AF-32 are potent antagonists and possess KD values in the same range as those of the more flexible congener 3-diphenylacetoxy-quinuclidine (AF-43) and atropine (0.6--2 nM) but with koff = 0.1 msec-1 (AF-41) and koff = 1 msec-1 (AF-43) (carp atrium). Thus, duration of drug action of drug action at the receptor is a function of structural rigidity in the drug molecule, termination of action being fastest with the flexible molecules. Differences in rigidity among various antagonists also find expression in an unequal distribution of potencies in various tests; thus the rigid antagonists differentiate between two central effects in mice, viz., prevention of oxotremorine-induced tremors and fall from the rotating rod by a factor of 1:20 (especially AF-41 versus AF-43), whereas the more flexible antagonists (AF-43, atropine or even 3-quinuclidinyl-benzilate) do not show such as a selectivity. The existence of heterogenous muscarinic receptors can be inferred from data presented. Both theoretical and practical implications are discussed.

Indirect modulation of cholinergic activity by cholinesterase inhibition is currently a widely established symptomatic treatment for Alzheimer's disease (AD). Selective activation of certain muscarinic receptor subtypes has emerged as an alternative cholinergic-based amyloid-lowering strategy for AD, as selective muscarinic M1 receptor agonists can reduce amyloid-β (Aβ) production by shifting endoproteolytic amyloid-β protein precursor (AβPP) processing toward non-amyloidogenic pathways. In this study, we addressed the hypothesis that acute stimulation of muscarinic M1 receptors can inhibit Aβ production in awake and freely moving AβPP transgenic mice. By combining intracerebral microdialysis with retrodialysis, we determined hippocampal Aβ concentrations during simultaneous pharmacological modulation of brain M1 receptor function. Infusion with a M1 receptor agonist AF102B resulted in a rapid reduction of interstitial fluid (ISF) Aβ levels while treatment with the M1 antagonist...

The M1 muscarinic acetylcholine receptor (M1ACh-R) is a G protein-coupled receptor that can occur in interconvertible coupled and uncoupled states. It is enriched in the basal ganglia, hippocampus, olfactory bulb, and cortical areas, and plays a role in motor and cognitive functions. Muscarinic M1 agonists are potential therapeutic agents for cognitive disorders. The aim of this study was to evaluate [11C]AF150(S) as a putative M1ACh-R agonist PET ligand, which, owing to its agonist properties, could provide a tool to explore the active G protein-coupled receptor. Regional kinetics of [11C]AF150(S) in rat brain were measured using a high-resolution research tomograph, both under baseline conditions and following pre-treatment with various compounds or co-administration of non-radioactive AF150(S). Data were analysed by calculating standard uptake values and by applying the simplified reference tissue model (SRTM). [11C]AF150(S) was rapidly taken up in the brain, followed by a rapid ...

Rigid analogs of acetylcholine (ACh) were designed for selective actions at muscarinic receptor subtypes. AF102B, AF125, AF150 and AF151 are such rigid analogs of ACh. Whilst AF125 is an M2 > M1 agonist, AF102B, AF150 and AF151 are centrally active M1 agonists. AF102B has a unique agonistic profile showing, inter alia, only part of the M1 electrophysiology of ACh and unusual binding parameters to mAChRs. AF150 and AF151 are more efficacious agonists than AF102B for M1 AChRs in rat cortex and in CHO cells stably transfected with the m1 AChR subtype. In various animal models for Alzheimer's disease (AD) all three agonists (AF102B, AF150 and AF151), and in particular AF102B, exhibited positive effects on mnemonic processes and a wide safety margin. Such agonists, and especially AF102B, can be considered as a rational treatment strategy in AD. Here we review some current features of these compounds, which may be relevant to a rational treatment strategy in AD. Comparison is made,...