SDZ ENS-163 IS A SELECTIVE M1 AGONIST AND INDUCES RELEASE OF ACETYLCHOLINE

In the present study some pharmacological properties of the new muscarinic agonist SDZ ENS 163; (+)-(3S,cis)-3-ethyldihydro-4-[(1-methyl-1H-imidazol-5-yl)methyl-2(3H)-thiophenonedihydrogenphosphate] have been investigated. In the rat superior cervical ganglion, a model for M1 muscarinic receptors, SDZ ENS 163 induced concentration-dependent depolarizations (pD2 = 6.5 +/- 0.3, efficacy = 128 +/- 4.2% compared to carbachol). SDZ ENS 163 was a very weak partial agonist with respect to M2 receptor-induced decrease in contractile force in rat left atria (efficacy = 14 +/- 2.9%). In addition. SDZ ENS 163 competitively antagonized the effect of carbachol in rat left atria (pA2 = 5.8 +/- 0.2). In the guinea-pig ileum SDZ ENS 163 was a partial agonist with respect to force of contraction mediated by M3 receptors (pD2 = 5.3 +/- 0.1; efficacy = 72 +/- 4.2%). The oxotremorine-induced inhibition of the electrically stimulated release of acetylcholine (ACh) in rat hippocampal slices was reversed by SDZ ENS 163 (pA2 = 5.5 +/- 0.1). In addition after oral administration SDZ ENS 163 (3 - 10-mu-mol/kg) reduced brain ACh levels, which is indicative of increased ACh turnover. Finally, increases in energy of the low frequency band (2 - 5 Hz) were observed in rat hippocampal EEG after intraperitoneal administration of SDZ ENS 163 (0.3 - 30-mu-mol/kg). We conclude that SDZ ENS 163 is a selective M1 agonist in vitro with an additional M2 antagonistic effect. The in vivo effects of SDZ ENS 163 may result both from postsynaptic M1 agonistic as well as M2 receptor antagonistic activity. The unique pharmacological profile of SDZ ENS 163 may prove clinically favourable for treatment of cognitive deficits

6-CARBOXYMETHYL-2-AZABICYCLO[2.2.1]HEPTANE ENANTIOMERS - MUSCARINIC ACTIVITIES OF RIGID ANALOGS OF ARECOLINE

(1R,4R,6R)-(-)-6-Carbomethoxy-2-azabicyclo[2.2.1]heptane 8a, (1R,4R,6R)-(-)-6-carbomethoxy-2-methyl-2-azabicyclo[2.2.l]heptane 2a and their enantiomers 8b and 2b have been prepared as rigid analogues of the enantiomorphic conformations of arecoline, and their activities as muscarinic agonists evaluated

6-carboxymethyl-2-azabicyclo[2.2.1]heptane enantiomers: Muscarinic activities of rigid analogues of arecoline

(1R,4R,6R)-(-)-6-carbomethoxy-2-azabicyclo[2.2.1]heptane 8a, (1R,4R,6R)-(-)-6-carbomethoxy-2-methyl-2-azabicyclo[2.2.1]heptane 2a and their enantiomers 8b and 2b have been prepared as rigid analogues of the enantiomorphic conformations of arecoline, and their activities as muscarinic agonists evaluated

Association between butyrylcholinesterase K variant and mild cognitive impairment in the Thai community-dwelling patients

Natsalil Pongthanaracht,1 Somchai Yanarojana,1 Darawan Pinthong,1 Supeenun Unchern,1 Amnuay Thithapandha,1 Prasert Assantachai,2 Porntip Supavilai11Department of Pharmacology, Faculty of Science, 2Department of Preventive and Social Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, ThailandObjective: To study the association of the butyrylcholinesterase K variant (BChE-K) and the plasma BChE activity with mild cognitive impairment (MCI) in Thai community-dwelling patients.Methods: One hundred patients diagnosed with MCI and 100 control subjects were recruited from the community-dwelling setting in Bangkok, Thailand. The genotype and allele distributions of the BChE-K were determined by polymerase chain reaction and subsequent DNA sequencing. The BChE activity was measured in plasma according to the Ellman’s method.Results: The BChE-K allele frequencies in the Thai community-dwelling patients were in accordance with other ethnics. The BChE-K allele frequency in the control subjects (12%) was higher than that of MCI patients (5.5%), suggesting a protective role of BChE-K for MCI in the Thai community-dwelling patients. The BChE-K homozygotes were significantly associated with lower BChE activity.Conclusion: Our results suggested that the BChE-K may be implicated as a protective factor for MCI in the Thai community-dwelling patients, although a further study with a large sample size is warranted to confirm this.Keywords: butyrylcholinesterase K variant, butyrylcholinesterase activity, mild cognitive impairment, Thai community-dwelling patient

Stereoisomerism and muscarinic receptor agonists: Synthesis and effects of the stereoisomers of 3-[5-(3-amino-1,2,4-oxadizol)yl]-1-azabicyclo[2.2.1]heptane

The preparation and the biological activities of the four stereoisomers of 3-[5-(3-amino-1,2,5-oxadiazol)yl]-1-azabicyclo [2.2.1]heptane are described. The most potent stereoisomer, 3a, has the 3R,4R configuration, and in vitro activities in (pD2(% efficacy): ileum 8.8 (87%), hippocampus 9.8 (116%) and ganglion 10.2 (36%)). 3b (3S,4S) was weaker (ileum 8.1 (121%), hippocampus 8.5 (107%), ganglion 9.0 (63%)). The other two stereoisomers, 4a (3S,4R; ileum 7.1 (108%), hippocampus 8.2 (116%), ganglion 7.3 (31%)) and 4b (3R,4S; ileum 7.0 (100%), hippocampus 7.0 (120%), ganglion 7.2 (67%)) are of comparable activity, with an analogous profile to that of the more potent stereoisomers. Thus, compounds 3a and 4a, possessing the 4R stereochemistry, showed selectivity for the hippocampus over the ileum. Compound 3a was, however, more potent in the ganglion than in the hippocampus. All four stereoisomers were full agonists in the hippocampus, indicating M1activity; however, they were partial agonists in the depolarisation of the rat superior cervical ganglion, another M1-mediated response. This may be due to M2-mediated hyperpolarization. With 3a (0.01 mg/kg i.p.), expression of c-fos mRNA was observed in the hypothalamus and in brain areas involved in sensory processing; these effects were totally blocked by pretreatment with 2 mg/kg scopolamine. In particular, activation of the superior colliculus is consistent with potent M2activity