Luigi Filocamo

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 Alzheimers 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.

Synthesis and structure-activity relationships of new acetylcholinesterase inhibitors: Morpholinoalkylcarbamoyloxyeseroline derivatives

Abstract Several new potent acetylcholinesterase inhibitors have been synthesised as potential drugs for the treatment of Alzheimers disease. Heptylphysostigmine (MF201) is a drug analogue of physostigmine under clinical evaluation. In order to obtain new physostigmine analogues, the methylcarbomoyloxy group was substituted with ω-morpholinoalkylcarbamoyloxy moieties of different chain lengths (C2–C12). Potent in vitro inhibition is seen when the chain length is composed of eight to twelve methylene groups. The inhibitory activity of the C10 and C11 is 7-fold greater with respect to heptylphysostigmine.

Novel locally active estrogens accelerate cutaneous wound healing. A preliminary study.

New 17beta-estradiol (E2) derivatives 1-11 were synthesized from an estrone derivative by addition of organometallic reagents prepared from protected alpha,omega-alkynols and further elaboration of the addition products. The estrogenic activity of these novel compounds was determined using in vitro binding competition assay and transactivation analysis. Among the E2 derivatives synthesized, compound 2 showed the highest transactivation potency and was therefore tested for its ability to modulate cutaneous wound healing in vivo. Compound 2s ability to accelerate wound healing in ovariectomized mice and decrease the production of inflammatory molecules was comparable to that of E2. However, the activity of compound 2 was not superimposable to E2 with regard to the cells involved in the wound repairing process. When locally administered, compound 2 did not show any systemic activity on ER. This class of compounds with clear beneficial effects on wound healing and suitable for topical administration may lead to the generation of innovative drugs for an area of unmet clinical need.

Synthesis of inositol phospholipids with thiophosphoester bonds

Abstract the synthesis of phosphatidylinositol (PI) analogues (±)1- O -(1- O -octadecanoyl-2- O -acetyl- rac -3-thioglycerylphosphoryl)- myo -inositol ( 7 ), (±)1- O -(1,2-di- O -octadecyl- rac -3-thioglycerylphosphoryl)- myo -inositol ( 14a ), (±)1- O -(1,2-di- O -octyl- rac -3-thioglycerylphosphoryl)- myo -inositol ( 14b ) and (±)1- O -(1- O -octadecyl-2- O -methyl- rac -3-thioglycerylphosphoryl)- myo -inositol ( 14c ) designed to show a novel mode of PI-phospholipase C (PI-PLC) inhibition, is described.

Synthesis of some thiophosphate analogues (C-S-P) of phosphatidylinositol

Abstract the synthesis of analogues of phosphatidylinositol (PI), designed to show a novel mode of PI-phospholipase C (PI-PLC) inhibition, is described.

Synthesis, binding affinity and selectivity of new β1- and β2-adrenoceptor blockers

Abstract The synthesis of a new series of sesamol derivatives with β-adrenergic blocking activity is described. The affinity and selectivity of these compounds for β1- and β2-adrenoceptors were studied in comparison with those of ICI-118551 and propranolol. Some of the synthesized compounds show very good affinity for the β2-receptors of rat lung membranes and two of them provide interesting selectivity.

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 and cytotoxic activity of (±) octadecylphosphodithionyl-1-myo-inositol

Abstract the synthesis of the phosphatidylinositol (PI) analogue (±)-octadecylphosphodithionyl-1- myo -inositol is described. The cytotoxic activity on K562 erythroleukaemic cells and the effect on the activity of PI specific phospholipase C (PI-PLC) from human platelets are reported.

Novel Locally Active Estrogens Accelerate Cutaneous Wound Healing-Part 2

Estrogen deprivation is associated with delayed healing, while estrogen replacement therapy (ERT) accelerates acute wound healing and protects against development of chronic wounds. However, current estrogenic molecules have undesired systemic effects, thus the aim of our studies is to generate new molecules for topic administration that are devoid of systemic effects. Following a preliminary study, the new 17β-estradiol derivatives 1 were synthesized. The estrogenic activity of these novel compounds was evaluated in vitro using the cell line ERE-Luc B17 stably transfected with an ERE-Luc reporter. Among the 17β-estradiol derivatives synthesized, compounds 1e and 1f showed the highest transactivation potency and were therefore selected for the study of their systemic estrogenic activity. The study of these compounds in the ERE-Luc mouse model demonstrated that both compounds lack systemic effects when administered in the wound area. Furthermore, wound-healing experiments showed that 1e displays a significant regenerative and anti-inflammatory activity. It is therefore confirmed that this class of compounds are suitable for topical administration and have a clear beneficial effect on wound healing.

Rational Design of New Acetylcholinesterase Inhibitors

Six different classes of drugs, theoretically, could be useful for the treatment of the cholinergic deficit which characterizes Alzheimer’s Disease (AD): Cholinesterase inhibitors (ChEI), which increase the synaptic levels of acetylcholine (ACh) by retarding its hydrolysis. ACh precursors, such as phosphatidylcholine, which might enhance the availability of choline. ACh releasers, which should facilitate the release of ACh from presynaptic end terminals, thereby activating the second messenger PIP2 hydrolysis. M1 and M3 receptor agonists, which mimic ACh on the postsynaptic end terminal receptors. M2 receptor antagonists (M2 generally are presynaptics and play a role in controlling ACh release via negative feedback). Nicotinic agonists or substances having nicotinic like effects, which should also favor the release of ACh.