Long chain analogs of physostigmine as potential drugs for Alzheimer's disease: new insights into the mechanism of action in the inhibition of acetylcholinesterase.

Heptylphysostigmine is in advanced clinical trial as a drug for Alzheimer's disease. 8-Morpholinooctylphysostigmine and 8-(cis-2,6-dimethylmorpholino)octylphysostigmine are currently undergoing pre-clinical evaluation. The mechanism of action of these compounds in the inhibition of acetylcholinesterase has been investigated. All the examined compounds display non competitive-like kinetics of inhibition. There are no reversible components in the observed inhibition: the whole inhibitory effect is due to the time-dependent pseudo-irreversible carbamylation of the active site. Yet the observed time course of the inhibition does not match a simple second order kinetics. An influence of the quaternary structure of the enzyme on the more complex kinetics of carbamylation is hypothesized. Reactivation experiments on the inhibited enzyme show long lasting inhibitory effects for these compounds. The higher duration of the anticholinesterase effect of the morpholino derivatives compared to heptylphysostigmine should provide the basis for their higher therapeutic potential.

Potentiation of cADPR-induced Ca(2+)-release by methylxanthine analogues.

Caffeine and other methylxanthines are known to induce Ca(2+)-release from intracellular stores via the ryanodine receptor. In the present work, a range of caffeine analogues, in which methyl groups at the 1 and 7 positions were replaced with alkyl chains containing different functional groups (oxo, hydroxyl, propargyl, ester, and acids), were synthesized. These compounds were then screened for their ability to potentiate Ca(2+)-release induced by cADPR (an endogenous modulator of ryanodine receptors) in sea urchin egg homogenates. Two of the synthesized methylxanthines, 1, 3-dimethyl-7-(7-hydroxyoctyl)xanthine (37) and 3-methyl-7-(7-oxooctyl)-1-propargylxanthine (66), were shown to be more potent than caffeine in potentiating cADPR-induced Ca(2+)-release, while 1,3-dimethyl-7-(5-ethylcarboxypentyl)xanthine (14) was shown to be more efficacious. The development of new methylxanthine analogues may lead to a better understanding of ryanodine receptor function and could possibly provide novel therapeutic agents.

Synthesis of some carbamates of myo-inositol.

The syntheses are described of the 1-O-carbamoyl (11), 1-O-carbamoyl-2-O-stearoyl (10), 1-O-(acetylcarbamoyl)-2-O-stearoyl (12), 1-O-(heptylcarbamoyl) (13), 2-O-(heptylcarbamoyl) (14) 1,2-di-O-(heptylcarbamoyl) (15), and 1-O-(octadecylcarbamoyl) (16) derivatives of myo-inositol. None of these compounds had significant activity against phospholipase C.

Synthesis of 2'-heptylcarbamoyloxy-2-methyl-6,7-benzomorphan: a new analogue of heptylphysostigmine (MF 201).

The synthesis of 2'-heptylcarbamoyloxy-2-methyl-6,7-benzomorphan is described. The compound is structurally related to the cholinesterase inhibitor heptylphysostigmine (MF 201) because the angular methyl group of the esoroline nucleus has been changed into a bridging carbon and the anilinic nitrogen has been replaced by a methylene group. This compound proved to be a potent cholinesterase in vitro inhibitor.

New 1,2,4-oxadiazole derivatives: synthesis and adrenergic receptors binding studies.

In order to obtain derivatives with simultaneous alpha- and beta-adrenergic blocking activity, compounds having the phenoxypropanolaminic structure of beta-adrenergic blockers have been synthesised, as well as 1,2,4-oxadiazole moiety, which could imitate the imidazolinic nucleus characteristic of drugs acting on alpha-adrenergic receptors. The synthesised compounds have been submitted to alpha and beta receptor binding assays. Some derivatives showed an alpha-adrenoceptor binding activity higher than labetalol and similar to prazosin, but with a poor beta-adrenoceptor binding activity.

Synthesis, binding affinity and selectivity of new beta 1- and beta 2-adrenoceptor blockers.

The synthesis of a new series of sesamol derivatives with beta-adrenergic blocking activity is described. The affinity and selectivity of these compounds for beta 1- and beta 2-adrenoceptors were studied in comparison with those of ICI-118551 and propranolol. Some of the synthesized compounds show very good affinity for the beta 2-receptors of rat lung membranes and two of them provide interesting selectivity.

Structure-activity relationships in open ansa-chain rifamycin S derivatives as inhibitors of HIV-1 reverse transcriptase.

Three types of open ansa-chain rifamycin S derivatives have been prepared: derivatives with the ansa-chain open at C(29) and the original dihydrofuranone ring; derivatives with the ansa-chain open at C(29) and a furane ring; derivatives with the ansa-chain at open NH-C(15). Only derivatives of the first type are weak inhibitors of HIV-1 reverse transcriptase (IC50 ca.300 microM) while derivatives of the two other types are inactive. It has been hypothesized that the active derivatives inhibit the viral enzyme interacting through the groups C(14)H3, C(13)H3, and C(1)O at the same site as the well-known inhibitors TIBO and Nevirapine. In particular C(13)H3 must be unhindered and in an appropriate position out of the plane containing the chromophore-rings. The open ansa-chain seems to play the role of a lipophylic substituent.

Rifamycins as inhibitors of retroviral reverse transcriptase from M-MuLV, RAV-2, and HIV-1.

29 Rifamycins were tested for inhibition of Reverse Transcriptase (RT) as potential anti HIV drugs. Two purified commercial enzymes from M-MuLV and RAV-2 were used. Anti-RT activity was also measured on a crude lysate of HIV-1. The results show that some derivatives have interesting levels of activity on isolated M-MuLV and RAV-2 RTs, while they are less active on the RT in the crude HIV-1 lysate. The active derivatives include oximes and hydrazones, alkylaminoderivatives, open ansa-chain derivatives and derivatives carrying a modified nucleoside.

Synthesis of phenothiazine derivatives as potential inhibitors of phospholipase C.

In order to study the structure-activity relationships of phenothiazine derivatives inhibiting phosphatidylinositol-specific phospholipase C (PI-PLC), the synthesis of some phenothiazine amide, amine and ester derivatives was performed mainly by reacting 10H-phenothiazine-10-propanoyl chloride with some amines and alcohols; the resulting amides were reduced with borane to yield the corresponding amines. Starting from 2-chloro and 2-trifluoromethyl-10H-phenothiazine-10-propanoyl chloride two amides were synthesized. The inhibiting activity on PI-PLC from human platelets is reported.