The pharmacological assessment of RS 86 (2-ethyl-8-methyl-2,8-diazaspiro-[4,5]-decan-1,3-dion hydrobromide). A potent, specific muscarinic acetylcholine receptor agonist

Palacios, J.M.; Bolliger, G.; Closse, Annemarie; Enz, Albert; Gmelin, G.; Malanowski, Jan

doi:10.1016/0014-2999(86)90082-8

Cited by 93 publications

(23 citation statements)

References 41 publications

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“…RS-86 presents high affinity and activity on both MI and M2 muscarinic receptor subtypes, though with a relatively higher activity on M1 systems (22,23). Central and peripheral cholinergic activity has been demonstrated in man at the doses employed in our study.…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of Direct and Indirectly Acting Cholinergic Agonists on Growth Hormone Release in Man, and Lack of Effect on Cortisol Secretion

Casanueva¹,

Villanueva²,

Cordido³

et al. 1989

J Neuroendocrinology

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Acetylcholine plays a key role in the modulation of growth hormone secretion. In fact, growth hormone release after provocative stimuli is blocked by muscarinic cholinergic antagonists, and conversely, indirect cholinergic agonists potentiate growth hormone secretion. To further understand the mechanism by which cholinergic pathways exert their effects, we have compared the growth hormone and cortisol secretion elicited on normal volunteers by pyridostigmine and by RS-86 (2-ethyl-8-methyl-2,8-diazaspiro-((4,5))-decan-1,3-dion hydrobromide). The former acts by inhibiting acetylcholinesterase, thus being an indirect muscarinic agonist, while the latter is a muscarinic receptor agonist which binds directly to and stimulates cholinergic receptors.In six subjects, pyridostigmine (120 mg PO) induced an increase of growth hormone of 11.0k2.4 pglL at 90 min, significantly greater than following placebo administration (1.4k0.3 pglt). In another group of five volunteers, RS-86 was administered in separate tests at a dose of 0.5, 1 and 2 mg PO. Growth hormone levels were not altered by any RS-86 dose compared with placebo values. Neither pyridostigmine nor RS-86 altered cortisol values.These results suggest that the mechanism of action of the cholinergic agonists is of great importance for their growth hormonereleasing capabilities, and question the accepted view of a cholinergic regulation of cortisol secretion in man.Acetylcholine, a key neurotransmitter, is assumed to regulate growth hormone (GH) secretion in both experimental animals and man (1-3). Antagonists of muscarinic receptors such as atropine or pirenzepine are able to completely abolish GH responses to arginine, physical exercise, clonidine, glucagon, sleep, L-dopa and opioid peptides (4-7). It is now generally accepted that muscarinic pathways regulate GH secretion by tonically inhibiting somatostatin release from the hypothalamus. Thus, the administration of cholinergic antagonists such as atropine would unblock the system, and the resulting somatostatin release would reduce the GH responses to different challenges (8-10). Conversely, cholinergic agonists would increase GH secretion by reducing tonic somatostatin release (I).Interestingly, if the data obtained about GH regulation with muscarinic antagonists have been clear-cut, findings with agonists have been less conclusive. Practically all the results have been obtained with indirect agonists, i.e. drugs which inhibit acetylcholinesterase activity (1 0). When direct agonists of muscarink receptors have been employed, the GH release was attributed to the powerful side effects of these drugs ( 1 1, 12), and in experimental animals direct cholinergic agonists did not stimulate GH release (13). Adrenocorticotrophin (ACTH) is the other pituitary hormone regulated by cholinergic synapses. It is commonly accepted that acetylcholine stimulates the corticotrophin-releasing factor (CRF)-ACTH-cortisol axis by acting at the hypothalamic level (14)(15)(16). However, the experimental data supporting a cholinerg...

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Section: Discussionmentioning

confidence: 99%

Differential Effects of Direct and Indirectly Acting Cholinergic Agonists on Growth Hormone Release in Man, and Lack of Effect on Cortisol Secretion

Casanueva¹,

Villanueva²,

Cordido³

et al. 1989

J Neuroendocrinology

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“…RS86 (gift from Novartis, Basel, Switzerland) is a putative muscarinic M1 receptor agonist (33)(34)(35). Based on previous studies (33,34) we selected a range of appropriate doses of RS86 to test in our behavioral paradigm.…”

Section: Methodsmentioning

confidence: 99%

Cognitive changes and modified processing of amyloid precursor protein in the cortical and hippocampal system after cholinergic synapse loss and muscarinic receptor activation

Lin

Georgievska

Mattsson

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

104

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A number of in vitro studies have shown that activation of muscarinic receptors by cholinergic agonists stimulates the nonamyloidogenic, ␣-secretase-processing pathway of amyloid precursor protein (APP). To determine whether increased cholinergic neurotransmission can modify the APP processing in vivo, we administered a muscarinic receptor agonist (RS86) to normal or aged rats and rats with severe basal forebrain cholinergic deficits (induced by 192 IgG-saporin). The levels of the cell-associated APP in neocortex, hippocampus, and striatum, as well as the secreted form of APP (APPs) in cerebrospinal fluid, were examined by Western blots. Additionally, we investigated the association between the altered APP levels and behavioral deficits caused by cholinergic lesions. We found that treatment with muscarinic receptor agonist resulted in decreased APP levels in neocortex and hippocampus and increased levels of APPs in cerebrospinal fluid. Regulation of APP processing by the muscarinic agonist treatment occurred not only in normal rats, but also in aged and cholinergic denervated rats that model this aspect of Alzheimer's disease. Interestingly, we found that elevation of APP in neocortex correlated with the cognitive deficits in water-maze testing of rats with cholinergic dysfunction. These data indicate that increased cholinergic neurotransmission can enhance nonamyloidogenic APP processing in intact and lesioned rats and that APP may be involved in cognitive performance. Progressive loss of cognition and memory is the predominant characteristic of Alzheimer's disease (AD) (1). In AD, among several pathological features, extracellular deposition of amyloid ␤ peptide (A␤), neuronal tangles, and marked cholinergic cortical afferent dysfunction are fundamental (2). In spite of an improved understanding of genetic correlates of AD, it is not understood how cognitive deficits, amyloid formation, and cholinergic degeneration may be interrelated. In this regard, a number of questions need to be elucidated, including whether amyloid precursor protein (APP) and its derivatives are involved in cognitive deficits and cholinergic dysfunction and, in turn, how the degenerating cholinergic system may influence the metabolism of APP. Trisomy 21 in Down's syndrome with an extra copy of the APP gene eventually causes AD-like neuropathology including cholinergic dysfunction and impaired cognition, suggesting a gene dose effect on the cholinergic system and cognitive processes (3, 4). Experimental studies reveal that cholinergic function is altered in trisomy-16 mice, considered an animal model of human Down's syndrome (5). Genetic studies show that transgenic mice overexpressing human APP can exhibit some learning and memory deficits with or without amyloid plaque formation (6-8), indicating a potential direct role of APP and A␤ in the cognitive deficits. In contrast, secreted forms of APP (APPs) have potent memory-enhancing effects and can block learning deficits induced by scopolamine (9). Intracerebroventricular (ICV) infusion o...

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“…These include AH 6405 (1,4,5,6 tetrahydro-5-phenoxy-pyrimidine) (Marshall 1970), pilocarpine (Caulfield and Stubtey 1982), and RS 86 (Palacios et al 1986). However, the separation between M-I and M-2 activity is not marked, and all these compounds show M-2 agonist activity.…”

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confidence: 98%

Assessment of the muscarinic receptor subtype involved in the mediation of pilocarpine-induced purposeless chewing behaviour

1989

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Purposeless chewing behaviour in rats was enhanced by intraperitoneal administration of the muscarinic agonists pilocarpine (1.0-8.0 mg/kg), RS 86 (0.5-0.8 mg/kg), oxotremorine (1-2 mg/kg) and arecoline (2-32 mg/kg), but not by nicotine (0.1-3.2 mg/kg). Chewing behaviour was also induced by the ICV administration of the muscarinic agonists carbachol (12.5-100 micrograms) and pilocarpine (50-200 micrograms), but not by the putative M-1 receptor agonist McN-A-343 (50-200 micrograms) or AH 6405 (100-200 micrograms). The muscarinic receptor antagonists scopolamine (0.01-0.1 mg/kg SC), benzhexol (0.075-2.5 mg/kg SC), secoverine (1-10 mg/kg SC), and dicyclomine (1.25-10 mg/kg SC) antagonised purposeless chewing behaviour induced by pilocarpine (4 mg/kg IP). AF-DX 116 (2.5-100 mg/kg SC), an M-2 antagonist, partially inhibited the actions of pilocarpine (4 mg/kg IP). Based on ED40 values the rank order of potency following IP administration was scopolamine greater than benzhexol greater than secoverine greater than dicyclomine greater than AF-DX 116. The ICV administration of the muscarinic antagonists N-methylscopolamine (2.5-10 micrograms) and oxyphenonium (10-40 micrograms) antagonised chewing behaviour induced by pilocarpine (4 mg/kg IP) in a dose-related manner. The M-2 antagonist 4-DAMP (40-160 micrograms ICV), as well as AF-DX 116 (40-160 micrograms ICV), also inhibited the effects of pilocarpine (40-160 micrograms ICV). The putative M-1 receptor antagonist pirenzepine (80-320 micrograms ICV) did not antagonise chewing behaviour induced by pilocarpine (4 mg/kg IP).(ABSTRACT TRUNCATED AT 250 WORDS)

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The pharmacological assessment of RS 86 (2-ethyl-8-methyl-2,8-diazaspiro-[4,5]-decan-1,3-dion hydrobromide). A potent, specific muscarinic acetylcholine receptor agonist

Cited by 93 publications

References 41 publications

Differential Effects of Direct and Indirectly Acting Cholinergic Agonists on Growth Hormone Release in Man, and Lack of Effect on Cortisol Secretion

Differential Effects of Direct and Indirectly Acting Cholinergic Agonists on Growth Hormone Release in Man, and Lack of Effect on Cortisol Secretion

Cognitive changes and modified processing of amyloid precursor protein in the cortical and hippocampal system after cholinergic synapse loss and muscarinic receptor activation

Assessment of the muscarinic receptor subtype involved in the mediation of pilocarpine-induced purposeless chewing behaviour

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