Henry Guzik

SCH 57790, a selective muscarinic M2 receptor antagonist, releases acetylcholine and produces cognitive enhancement in laboratory animals

The present studies were designed to assess whether the novel muscarinic M(2) receptor antagonist 4-cyclohexyl-alpha-[4[[4-methoxyphenyl]sulphinyl]-phenyl]-1-piperazineacetonitrile (SCH 57790) could increase acetylcholine release in the central nervous system (CNS) and enhance cognitive performance in rodents and nonhuman primates. In vivo microdialysis studies show that SCH 57790 (0.1-10 mg/kg, p.o.) produced dose-related increases in acetylcholine release from rat hippocampus, cortex, and striatum. SCH 57790 (0.003-1.0 mg/kg) increased retention times in young rat passive avoidance responding when given either before or after training. Also, SCH 57790 reversed scopolamine-induced deficits in mice in a passive avoidance task. In a working memory operant task in squirrel monkeys, administration of SCH 57790 (0.01-0.03 mg/kg) improved performance under a schedule of fixed-ratio discrimination with titrating delay. The effects observed with SCH 57790 in behavioral studies were qualitatively similar to the effects produced by the clinically used cholinesterase inhibitor donepezil, suggesting that blockade of muscarinic M(2) receptors is a viable approach to enhancing cognitive performance.

Muscarinic agonists and antagonists in the treatment of Alzheimer's disease☆

Alzheimers disease (AD) is a neurodegenerative disease characterized by cognitive impairment and personality changes. The development of drugs for the treatment of the cognitive deficits of AD has focused on agents which counteract loss in cholinergic activity. Although symptoms of AD have been successfully treated with acetylcholinesterase inhibitors (tacrine, donepezil. rivastigmine, galanthamine), limited success has been achieved with direct M1 agonists, probably due to their lack of selectivity versus other muscarinic receptor subtypes. Muscarinic M2 antagonists have been reported to increase synaptic levels of acetylcholine after oral administration to rats (e.g. BIBN-99, SCH-57790), but their selectivity versus other muscarinic receptor subtypes is modest. Exploration of a series of piperidinylpiperidines has yielded the potent and selective M2 antagonist SCH-217443. This antagonist has excellent bioavailability in rats and dogs and shows activity in a rat model of cognition.

SCH 57790: A novel M2 receptor selective antagonist

As a decrease in cholinergic neurons has been observed in Alzheimers Disease (AD), therapeutic approaches to AD include inhibition of acetylcholinesterase to increase acetylcholine levels. Evidence suggests that acetylcholine release in the CNS is modulated by negative feedback via presynaptic M2 receptors, blockade of which should provide another means of increasing acetylcholine release. Structure-activity studies of [4-(phenylsulfonyl)phenyl]methylpiperazines led to the synthesis of 4-cyclohexyl-alpha-[4-[[4-methoxyphenyl]sulfinyl]-phenyl]-1-piperazin eacetonitrile. This compound, SCH 57790, binds to cloned human M2 receptors expressed in CHO cells with an affinity of 2.78 nM; the affinity at M1 receptors is 40-fold lower. SCH 57790 is an antagonist at M2 receptors expressed in CHO cells, as the compound blocks the inhibition of adenylyl cyclase activity mediated by the muscarinic agonist oxotremorine. This compound should be useful in assessing the potential of M2 receptor blockade for enhancement of cognition.

Borane Reduction of indoles with secondary amine substituents in a 2,3-fused side-chain

Abstract Trifluoroacetic acid treatment of the borane adducts of indoles with 2,3-fused side-chains containing secondary amines leads to the trans -indolines via intramolecular hydride transfer.

A synthesis of nikkomycin Z: Improved synthesis and protection of the pyridyl γ-hydroxy-α-aminobutanoic acid component☆

Abstract The first synthesis of nikkomycin Z is described. An improvement of the isoxazoline-based methodology, and an effective method for protection of 1b were devised. The application of oxalyditriazole (23) for peptide coupling proved most effective in completing the synthesis. A new and efficient synthesis of the prorequisite pyridyl E -olefin ( 5 ) is also described.

Dopamine receptor binding properties of some 2,3,4,5-tetrahydro-1H-3-benzazepine-7-ols with non-aromatic substituents in the 5-position

Abstract 2,3,4,5-tetrahydro-1H-3-benzazepine-7-ols related to the selective dopamine D-1 antagonist SCH 23390, but bearing non-aromatic substituents in the 5-position possess considerable affinity and selectivity for D-1 vs. D-2 receptors.

Diphenyl sulfoxides as selective antagonists of the muscarinic M2 receptor

Structure activity studies on [4-(phenylsulfonyl)phenyl]methylpiperazine led to the discovery of 4-cyclohexyl-alpha-[4-[[4-methoxyphenyl(S)-sufinyl]phenyl]-1-pi perazineacetonitrile, 1, an M2 selective muscarinic antagonist. Affinity at the cloned human M2 receptor was 2.7 nM; the M1/M2 selectivity is 40-fold.

Synthesis and antifungal activity of the 2,2,5-tetrahydrofuran regioisomers of SCH 51048.

The four 2,2,5-regioisomer counterparts of SCH 51048 were synthesized and evaluated. As with the parent series, only the two cis isomers possessed any in vitro activity, and only the activity of the isomer with the R-configuration at the tetrahydrofuran 2-carbon was significant. The activity data suggests that oxygen at only one of the two possible ring positions benzylic to the difluorobenzene participates usefully in active site binding.

trans-Reduction of 5-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole. X-Ray crystallographic study of the geometry of an intermolecular N–H ⋯ phenyl hydrogen bond

The stereochemistries of the two isomeric products (5) and (6) obtained in equal amounts from trans-reduction of 3-benzyl-5-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (3) have been determined by spectral and single-crystal X-ray analyses. Monoclinic crystals of (5) belong to space group P21/c, with a= 22.005(10), b= 10.270(5), c= 13.577(7)A, β= 106.42(1)°, Z= 8. The crystal structure was solved by direct methods, and atomic positional and thermal parameters refined by least-squares calculations to R 0.051 over 3 293 reflections measured by diffractometer. The two molecules defining the asymmetric crystal unit have identical conformations and are associated in a like manner in the solid state by N–H ⋯ N (mean N ⋯ N 3.26 A) and N–H ⋯ phenyl (mean calculated H ⋯ phenyl 2.32 A) hydrogen bonds.