Fernando Barzaghi

1-Alkyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-alkyl-oximes : a new class of potent orally active muscarinic agonists related to arecoline

Abstract On the basis of the knowledge acquired from basic studies of several known arecoline derivatives about the structural requirements for potent agonistic activity and oral efficacy, a series of 1-alkyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde- O -alkyl-oximes was synthesized and biologically evaluated in a battery of in vitro and in vivo assays. The most interesting molecules to emerge from the primary screening, 1,2,5,6-tetrahydropyridine-3-carboxaldehyde- O -methyloxime hydrochloride ( 11 , RU 35963), 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde- O -methyloxime hydrochloride ( 12 , RU 35926), and 1,2,5,6-tetrahydropyridine-3-carboxaldehyde- O -propargyloxime hydrochloride ( 30 , RU 47029) and 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxaldehyde- O -propargyloxime hydrochloride ( 33 , RU 35986), were evaluated more extensively, and their cholinomimetic profile was compared with that of the parent molecule, arecoline. The pharmacological results after oral administration to mice and rats revealed that their efficacy is 2–3 orders of magnitude higher than that of arecoline, and, in addition, they show a longer duration of action. The 4 aldoximes showed anti-amnesic properties in many respects superior to those of arecoline. Their anti-amnesic doses were 2 orders of magnitude lower than those inducing obvious cholinergic symptoms, and 3–5 orders of magnitude lower than the lethal doses. These new compounds can be regarded as potential candidates for clinical studies in AD (Alzheimers disease) patients.

Gastric anti-secretory, anti-ulcer and cytoprotective properties of substituted (E)-4-phenyl- and heteroaryl-4-oxo-2-butenoic acids

Abstract A class of anti-secretory, anti-ulcer and cytoprotective agents, the substituted (E) -4-phenyl and heteroaryl-4-oxo-2-butenoic acids, is described. This chemical structure is not related to those of any known anti-cholinergic drugs, histamine H 2 -receptor antagonists or prostaglandins. Five compounds, 4-(2-methoxyphenyl)- 15 , 4-(4-methoxyphenyl)- 22 , 4-(3,4-dimethoxyphenyl)- 32 , 4-(3,4,5-trimethoxyphenyl)- 40 , and 4-(2-furanyl)-4-oxo-2-butenoic acid 44 , have cytoprotective activity at a very low dose (0.6 mg/kg, p.o. ) and anti-secretory and anti-ulcer activities at higher doses. One of these compounds, RU 38086 40 , has been selected for clinical evaluation.

Amnesia-reversal activity of a series of 5-alkoxy-1-arylsulfonyl-2-pyrrolidinones

Abstract A series of 5-alkoxy-1-arylsulfonyl-2-pyrrolidinones were prepared by condensation of arylsulfonyl chlorides with 5-alkoxy-2-pyrrolidinones. Most compounds reversed electroconvulsive shock-induced amnesia in mice, showing the typical inverted U-shaped dose-response curve. The results for 58 compounds indicate that the potency is maximal when there is a 5-ethoxy group and progressively declines as the ether alkyl chain is either elongated or shortened. Substitution on the phenyl ring or its replacement with heterocyclic rings or its hydrogenation decreases the activity. The most promising compounds, with anti-amnesic properties superior in many respects (greater potency, greater efficacy and broader active dose-range) to those of piracetam and aniracetam were further evaluated for reversing scopolamine-induced amnesia and for their anti-hypoxic activity. 5-Ethoxy-1-phenylsulfonyl-2-pyrrolidinone ( 1 ) and 5-(1-methylethoxy)-1-/3-(trifluoromethyl) phenylsulfonyl/-2-pyrrolidinone ( 41 ) were selected for further evaluation because of their potent anti-amnesic and/or antihypoxic activity.

1-substituted-1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-alkyloximes as novel orally active and long-lasting muscarinic cholinergic agonists

Abstract Our previous attempts to design muscarinic agonists related to arecoline with the prerequisites for clinical use were successful with the discovery of 1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime hydrochloride, RU 35963, and structurally related compounds, in which the metabolically labile ester group of arecoline was replaced with the bioisosteric and stable aldoxime group. With the aim of obtaining compounds with improved cholinomimetic properties, several aryl- and alkyl-carbamates of RU 35963, as well as O-alkyl-, and O-aryl-carbamates of the 1-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxaldehyde-O-methyloxime hydrochloride, 24 , have been synthesized and evaluated biologically. The most interesting molecules to emerge from the primary screening have been evaluated more extensively and their cholinomimetic profiles compared with those of the parent molecules. In vitro studies indicate that none of these prodrugs have affinity for muscarinic receptor sites and some of them (aryl-carbamates) have cholinesterase inhibiting properties. Results from in vivo experiments in mice and rats showed that these new substances, 1-[4-chlorophenyl] oxycarbonyl-1,2,5,6-tetrahydropyridine-3- carboxaldehyde-O-methyloxime ( 16 = RU 47213) in particular, have cholinomimetic properties that compare favourably with those of the parent compounds. After oral administration 16 was clearly superior to RU 35963 in terms of central selectivity, duration of action and therapeutic indexes.

Amnesia-reversal activity of a series of 5-alkoxy-1-arylcarbonyl-2-pyrrolidinones and 5-alkoxy-1-arylmethyl-2-pyrrolidinones

Abstract A series of 5-alkoxy-1-arylcarbonyl-2-pyrrolidinones ( 1–27 ) were prepared by condensation of arylcarbonyl chlorides with 5-alkoxy-2 pyrrolidinones in the presence of butyl lithium in tetrahydrofuran. Alkylation of these intermediates with substituted benzyl bromides or chlorides, under solid/liquid phase-transfer conditions (KOH/Bu 4 NBr) in tetrahydrofuran, yielded 5-alkoxy-1-arylmethyl-2-pyrrolidinones ( 28–48 ). In the first series, the compounds with a 5- n -pentyloxy group had maximal ECS-induced amnesia reversing activity in mice, and in the second series, those with a 5- n -octyloxy group. In both series, substitutions on the phenyl ring had detrimental effects. The two most promising compounds 1-benzoyl-5- n -pentyloxy-2-pyrrolidinone ( 14 ) and 1-benzyl-5- n -octyloxy-2-pyrrolidinone ( 37 ) were more potent than piracetam and aniracetam and active over broader dose ranges: 50–200 and 50–400 mg/kg, po . Both compounds also reversed scopolamine-induced amnesia in mice, from 50 to 400 mg/kg, po ( 14 ) and from 100 to 400 mg/kg, po ( 37 ). Finally, 37 showed remarkable activity in protecting the mouse brain against chemically induced hypoxia, with a minimal effective dose of 50 mg/kg, ip , or 100 mg/kg, ip , in NaNO 2 - or KCN-induced hypoxia.