Stereoselective Increase in Cholinergic Transmission by R-(+)-hyoscyamine

Ghelardini, Carla; Gualtieri, Fulvio; Romanelli, Maria Novella; Angeli, Piero; Pepeu, Giancarlo; Giovannini, Maria Grazia; Casamenti, Fiorella; Malmberg-Aiello, P.; Giotti, A; Bartolini, Alessandro

doi:10.1016/s0028-3908(97)83761-6

Cited by 22 publications

(24 citation statements)

References 45 publications

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“…Because very low doses of atropine have selective inhibitory effects only on M 2 receptors, while usual doses have specific M 1 and M 2 inhibitory activity, Ghelardini et al [80] deduced the dose-related behavior of atropine, might be due to different activity of its two enantiomers. They found that R-(+) and S-(-)-hyoscyamine have different stereochemical requirements on muscarinic presynaptic autoreceptors and muscarinic postsynaptic receptors Fig.…”

Section: Analgesia Induced By Enhancers Of Ach Releasementioning

confidence: 99%

Analgesic and Antineuropathic Drugs Acting Through Central Cholinergic Mechanisms

Bartolini¹,

Mannelli²,

Ghelardini

2011

RPCN

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The role of muscarinic and nicotinic cholinergic receptors in analgesia and neuropathic pain relief is relatively unknown. This review describes how such drugs induce analgesia or alleviate neuropathic pain by acting on the central cholinergic system. Several pharmacological strategies are discussed which increase synthesis and release of acetylcholine (ACh) from cholinergic neurons. The effects of their acute and chronic administration are described. The pharmacological strategies which facilitate the physiological functions of the cholinergic system without altering the normal modulation of cholinergic signals are highlighted. It is proposed that full agonists of muscarinic or nicotinic receptors should be avoided. Their activation is too intense and un-physiological because neuronal signals are distorted when these receptors are constantly activated. Good results can be achieved by using agents that are able to a) increase ACh synthesis, b) partially inhibit cholinesterase activity c) selectively block the autoreceptor or heteroreceptor feedback mechanisms. Activation of M1 subtype muscarinic receptors induces analgesia. Chronic stimulation of nicotinic (N1) receptors has neuronal protective effects. Recent experimental results indicate a relationship between repeated cholinergic stimulation and neurotrophic activation of the glial derived neurotrophic factor (GDNF) family. At least 9 patents covering novel chemicals for cholinergic system modulation and pain control are discussed.

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Section: Analgesia Induced By Enhancers Of Ach Releasementioning

confidence: 99%

Analgesic and Antineuropathic Drugs Acting Through Central Cholinergic Mechanisms

Bartolini¹,

Mannelli²,

Ghelardini

2011

RPCN

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“…The compounds showed modest muscarinic antagonism on all five subtypes and did not possess any interesting subtype selectivity. There were three rein Table 1, the enantiomers, unlike the hyoscyamine enantiomers [3], were nearly equipotent, lakking enantioselectivity on all five muscarinic receptors. Compounds 1 (50-300 pg kg-' i.p.)…”

Section: Resultsmentioning

confidence: 98%

“…Recently we have reported the analgesic and cognition enhancing activity of a series of compounds derived from R-(+)-hyoscyamine [1][2][3] among which were several ring-substituted 2-phenylpropionic acid esters with general structure A. Within this class, on the basis of its interesting pharmacological profile, compound 9 (PG 9) was singled out to be studied in more details [2].…”

Section: Introductionmentioning

confidence: 99%

Binding Profiles of a Series of 2-Arylpropionic Acid Esters on Cloned Human Muscarinic Receptor Subtypes (m1-m5) and Their Relationship to Nootropic Activity

Ghelardini¹,

Mizuma²,

Gualtieri³

et al. 2011

Arzneimittelforschung

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The muscarinic binding profile of a series of 2-arylpropionic acid esters on cloned human muscarinic receptor subtypes (m1-m5) was determined to investigate whether there is a correlation between pharmacological activity and muscarinic receptor subtype selectivity. Among the tested compounds, 1, 7 and 9 showed the highest affinity for the m2 and m4 receptors. Compounds 1, 7 and 9 show good affinity for m4 receptors (pKi = 7.87; 7.73 and 7.10, respectively) and are able to discriminate 10-60 fold between m4/m1, m4/m3, and m4/m5 subtypes. Conversely, these compounds are able only to weakly discriminate between m4/m2. Compounds 1 (50-300 micrograms kg-1 i.p.) and 7 (1-10 micrograms kg-1 i.p.), injected 20 min before the training session, are able to prevent the amnesia induced by dicyclomine (2 mg kg-1 i.p.) in the mouse passive-avoidance test. Compounds 1 and 7, at the highest antiamnesic doses, do not modify motor coordination and spontaneous motility as evaluated by the rota-rod test and Animex apparatus experiments.

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“…The administration of scopolamine, an unselective muscarinic ACh receptor antagonist, results in impaired learning and memory in humans [Frumier et al, 1976] and animals [Levin and Bowman 1986]. Animals treated with the M 1 selective antagonist pirenzepine and dicyclomine had impaired memory processes in various paradigms in both mice and rats [Caufield et al, 1983;Sala et al, 1991;Ghelardini et al, 1997]. Furthermore, the administration of nicotinic ACh receptor antagonists, such as mecamylamine, produces a dose-dependent impairment of performance in the passive avoidance test [Elrod and Buccafusco, 1981].…”

Section: Discussionmentioning

confidence: 99%

The novel nootropic compound DM232 (UNIFIRAM) ameliorates memory impairment in mice and rats

Ghelardini

Galeotti

Gualtieri

et al. 2002

Drug Development Research

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The favorable pharmacological profile exhibited by piracetam stimulated the synthesis of related compounds potentially endowed with a higher nootropic potency. The antiamnesic and procognitive activity of DM232 (unifiram), a new compound structurally related to piracetam, was investigated. Mouse passive avoidance and rat Morris water maze and Social learning tests were employed. DM232 (0.001-1 mg kg À1 i.p. -0.01-0.1 1 mg kg À1 p.o.) prevented amnesia induced by scopolamine (1.5 mg kg À1 i.p.), mecamylamine (20 mg kg À1 i.p.), baclofen (2 mg kg À1 i.p.), and clonidine (0.125 mg kg À1 i.p.). Furthermore, The antiamnesic effect of the investigated compound was comparable to that exerted by well-known nootropic drugs such as piracetam (30-100 mg kg À1 i.p.), aniracetam (100 mg kg À1 p.o.), rolipram (30 mg kg À1 p.o.), and nicotine (5 mg kg À1 i.p). DM232 (0.1 mg kg À1 i.p.) was also able to prevent amnesia induced by scopolamine (0.8 mg kg À1 i.p.) in the rat Morris watermaze test. In the rat social learning test, DM232 (0.1 mg kg À1 i.p.) injected in adults rats reduced the duration of active exploration of the familiar partner in the second session of the test. DM232, similarly to piracetam, reduced the duration of hypnosis induced by pentobarbital. At the highest effective doses, the investigated compound did not impair motor coordination (rota rod test), nor modified spontaneous (Animex). These results indicate DM232 (unifiram) as a novel cognition enhancer, strictly related to piracetam-like compounds, able to ameliorate memory impairment at doses about 1,000 times lower than the most active available nootropic compounds. Drug Dev.

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Stereoselective Increase in Cholinergic Transmission by R-(+)-hyoscyamine

Cited by 22 publications

References 45 publications

Analgesic and Antineuropathic Drugs Acting Through Central Cholinergic Mechanisms

Analgesic and Antineuropathic Drugs Acting Through Central Cholinergic Mechanisms

Binding Profiles of a Series of 2-Arylpropionic Acid Esters on Cloned Human Muscarinic Receptor Subtypes (m1-m5) and Their Relationship to Nootropic Activity

The novel nootropic compound DM232 (UNIFIRAM) ameliorates memory impairment in mice and rats

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