Effect of Novel Amino Acids and Dipeptides Substituted 3-Morpholino Arecoline Derivatives as Muscarinic Receptor 1 Agonists in Alzheimer’s Dementia Models

A series of novel, potent and selective muscarinic receptor 1 agonists (M1 receptor agonists) that employ a key N-substituted morpholine arecoline moiety has been synthesized as part of research effort for the therapy of Alzheimer’s diseases. The ester group of arecoline (which is reported as mucarinic agonist) has been replaced by N-substituted morpholine ring. The structure activity relationship reveals that the increase in lipophilic carbon chain on the nitrogen atom of the morpholine ring increases the affinity of M1 receptor. In the present study, we are reporting N-amino acid substituted 9(a–k) and dipeptides substituted 10(a–j) and 11(a–j) morpholino arecoline derivatives, along with their in vitro muscarinic binding studies by using [³H]QNB and also in vivo evaluation of memory and learning in male Wistar rats (passive avoidance test plus maze studies) as M1 receptor agonist. Some molecules from the dipeptide series (10b, 10c and 10j) showed potent M1 receptor agonist activity. Other derivatives also showed considerable M1 receptor binding affinity.     

Interaction of enkephalins and des-tyrosyl-enkephalins with synaptosomal plasma membrane vesicles: enkephalin binding and inhibition of proline transport

Leucine- and methionine-enkephalins inhibit the Na+-dependent transport of proline into plasma membrane vesicles derived from synaptosomes. Glycine transport is weakly inhibited by enkephalins whereas there is no inhibition of transport of glutamic acid, aspartic acid, or gamma-aminobutyric acid. The inhibition of proline uptake is observed with des-tyrosyl-enkephalins but not with morphine, dynorphin(1-13), or beta-endorphins. Furthermore, enkephalin-induced inhibition of proline transport is not antagonized by naloxone. [Leu]enkephalinamide and modified [Leu]enkephalins with greater selectivity for the delta-subclass of enkephalin binding sites are less effective than [Leu]enkephalin in the inhibition of proline transport. Specific binding of [3H]Leu-enkephalin to the plasma membrane vesicles is demonstrated, and des-Tyr-[Leu]enkephalin competes with Leu-enkephalin for [Leu]enkephalin binding sites. The similarity in the concentrations of des-Tyr-[Leu]enkephalin required to compete for specific [Leu]enkephalin binding and to inhibit proline transport suggests that a specific subclass of enkephalin binding sites, distinguished by their recognition of both the enkephalins and their des-tyrosyl derivatives, may be associated with the synaptic proline transport system.     

Identification in Tetrahymena pyriformis of 3-hydroxy-3-methyl glutaryl coenzyme a lyase: its purification and properties

The major HMG-CoA utilizing enzyme activity in T. pyriformis has been determined to be HMG-CoA lyase. The enzyme was purified 32-fold to a specific activity of 431 units/mg from a mitochondrial fraction. Sephacryl S-200 chromatography gave an estimated molecular weight of 50,000 daltons for the HMG-CoA lyase. SDS gel electrophoresis revealed two bands stained by Coomassie Blue--a major band of 50,000 daltons and a minor band of 25,000 daltons. The latter is believed to be an impurity in the preparation. The enzyme has a pH optimum of 9.0, is stimulated slightly by sulfhydryl reagents, and requires a divalent cation for maximum activity. The KM for HMG-CoA is 15 microM.     

A comparative study of the effects of aflatoxin B1, alpha-amanitin and actinomycin-D on RNA synthesis by rat liver.

The effect of different combinations of aflatoxin B1, alpha-amanitin and actinomycin-D on the incorporation of orotic acid-6-14C into RNA was investigated using rat liver slices. The results support the view that the mode of action of aflatoxin B1 and alpha-amanitin are similar in some respects, and that aflatoxin B1 and actinomycin-D act according to different mechanisms. Evidence was also obtained about the formation of an active metabolite of aflatoxin B1 in this system.     

Effects of pisatin on Dictyostelium discoideum: its relationship to inducible resistance to nystatin and extension to other isoflavonoid phytoalexins

Dictyostelium discoideum amoebae can acquire resistance to otherwise inhibitory concentrations of pisatin, an isoflavonoid phytoalexin of pea, and nystatin, a polyene antibiotic, following pretreatment with sublethal concentrations of these compounds. Additionally, growth on medium containing pisatin can induce nystatin resistance. We show here that distinct mechanisms mediate the inducible resistance to these two compounds because it is possible to isolate mutations that specifically block the induction of nystatin resistance but do not affect the induction of pisatin resistance. Pisatin did not affect wild-type sterol biosynthesis; therefore, the induction of nystatin resistance by pisatin is probably not via an alteration of membrane sterols. The inducible pisatin resistance phenotype was shown to extend to the isoflavonoid phytoalexins maackiain and biochanin A, and all three compounds inhibited the aggregation of amoebae that is normally triggered by starvation. Received: 23 February 1998 / Accepted: 26 June 1998