Francesco Claudi

Dimeric L-Dopa Derivatives as Potential Prodrugs

A series of dimeric derivatives (+)-1, and (+)-2, and (+)-3a-d of L-Dopa diacetyl esters was synthesized and evaluated as potential L-Dopa prodrugs with improved physicochemical properties. All the new compounds showed chemical stability in aqueous buffer solutions (pH 1.3 and 7.4). A relatively slow release of L-Dopa in human plasma was observed.

Synthesis of L-(+)-3-(3-hydroxy-4-pivaloyloxybenzyl)-2,5-diketomorpholine as potential prodrug of L-Dopa

The synthesis and in vitro chemical and enzymatic stability of L-(+)-3-(3-hydroxy-4-pivaloyloxybenzyl)-2,5-diketomorpholine (9) as L-Dopa prodrug are described. Prodrug 9 possesses a good lipophilicity (log P = 2.153 +/- 0.017), is stable in aqueous buffer solutions (pH 1.3 and 7.4), and in 80% rat and human plasma it is turned into L-Dopa.

Design, synthesis, and preliminary pharmacological evaluation of new imidazolinones as L-DOPA prodrugs.

L-DOPA, the immediate biological precursor of dopamine, is still considered the drug of choice in the treatment of Parkinsons disease. However, therapy with L-DOPA is associated with a number of acute problems. With the aim to increase the bioavailability after oral administration, we designed a multi-protected L-DOPA prodrugs able to release the drug by both spontaneous chemical or enzyme catalyzed hydrolysis. The new compounds have been synthesized and preliminarily evaluated for their water solubility, log P, chemical stability, and enzymatic stability. The results indicate that the incorporation of the amino acidic moiety of L-DOPA into an imidazoline-4-one ring provides prodrugs sufficiently stable to potentially cross unchanged the acidic environment of the stomach, and to be absorbed from the intestine. They also might be able to release L-DOPA in human plasma after enzymatic hydrolysis. The ability of prodrugs 6a-b to increase basal levels of striatal DA, and influence brain neurochemistry associated with dopaminergic activity following oral administration, as well as the radical-scavenging activity against DPPH for compounds 6a-b and 15a are also reported.

3-[2-[4-(4-Fluorobenzoyl)piperidin-1-yl]ethyl]-5,6,7,8-tetrahydro-4(3H)quinazolinones: serotonin 5-HT2A receptor antagonists endowed with potent, central action

Summary A series of 5,6,7,8-tetrahydro-4(3 H )-quinazolinones substituted at the 3-position with 4-benzoyl-1-ethylpiperidine, 4-(4-fluorobenzoyl)-1-ethylpiperidine, 4-[bis-(4-fluorophenyl)methylene]-1-ethylpiperidine, or 4-(4-fluorophenyl)-1-propylpiperazine have been prepared and evaluated in binding assays to determine their affinity at serotonin 5-HT 2A receptors as well as in a functional test, ie, wet dog shakes (WDS) induced by L-5-hydroxytryptophan (L-5-HTP), a behavioural response which is mediated by stimulation of 5-HT 2A receptors. Among the compounds prepared, 3-[2-[4-(4-fluorobenzoyl)piperidin-l-yl]ethyl]-5,6,7,8-tetrahydro4 (3 H )-quinazolinone ( 10a ) and 2-methyl-3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-5,6,7,8-tetrahydro-4(3 H )-quinazolinone ( 10b ) proved to be the most potent 5-HT 2A receptor antagonists. In binding assays, the two compounds displayed similar affinity for 5-HT 2A receptors in the nanomolar range to ketanserin and ritanserin. In the WDS test, they were even more potent than ketanserin and ritanserin. Compound 10b , which was found to possess the highest potency and duration of action in the WDS test, was chosen for a preliminary evaluation of its ability to inhibit ethanol intake in rats, a response linked to blockade of the central 5-HT 2A receptors. This compound significantly reduced ethanol intake in rats from the first day of treatment. The results of the present study indicate that 10b is a potent centrally acting antagonist at 5-HT 2A receptors.

Behavioural evidence for central D-2 dopamine receptor agonistic effect by some 2-(fluorohydroxyphenyl)ethylamines.

The IP injection of 2-(4-fluoro-3-hydroxyphenyl)ethylamines. (FDA 24), N-n-propyl-N-(2-phenylethyl)-2-(3-fluoro-4-hydroxyphenyl)ethylamine (FDA 27F) and N-n-propyl-N-(2-phenylethyl)-2-(4-fluoro-3-hydroxyphenyl) ethylamine (FDA 40) into adult male rats induced the stretching and yawning (SY) syndrome, FDA 24 being the least active. Moreover, FDA 27F and FDA 40 potentiated penile erection (PE) with respect to controls. For both signs (PE and SY), FDA 40 was the most potent of the three compounds. These effects, which are considered typical signs of central D-2-dopamine (DA) receptor stimulation, were dose-related and significantly inhibited by pretreatment with the selective D-2 DA antagonist, sulpiride, but not by domperidone, which does not cross the hematoencephalic barrier. In previous binding studies, FDA 27F and FDA 40 showed high affinity and selectivity for D-2 DA receptors, while FDA 24 had a low affinity for both D-1 and D-2 DA receptors. The present data show that FDA 27F and FDA 40 cross the blood-brain barrier and exert an agonistic effect on the central D-2 DA receptors. These results also provide evidence of the value of PE and SY tests as sensitive tools for the study of DA-neurochemical mechanisms.

Indolizine derivatives with biological activity VI 1-(2-aminoethyl)-3-benzyl-7-methoxy-2-methylindolizine, benanserin structural analogue

In continuing the search for new biologically active agents in the indolizine field, 1-(2-aminoethyl)-3-benzyl-7-methoxy-2-methyl-indolizine was synthesized and evaluated for its in vitro activities on smooth muscle. Anti-histamine, anti-acetylcholine and anti-5-hydroxytryptamine activities, in comparison to those of the indole analogue benanserin, are reported.

Benzimidazole, Benzoxazole and Benzothiazole Derivatives as 5HT2B Receptor Ligands. Synthesis and Preliminary Pharmacological Evaluation

2-Phenethylbenzimidazole, 2-phenethylbenzoxazole and 2-phenethylbenzothiazole derivatives were synthesized to explore the structural features of the serotonin 5-HT2B receptor antagonists. Those molecules were designed to recognize the 5-HT2B receptor and to discriminate it from the 5-HT2A and 5-HT2C subtypes. All compounds were characterized by binding affinity determination for 5-HT2A and 5-HT2C subtypes and antagonistic activity for 5-HT2B receptor in rat stomach fundus. None of the new compounds showed affinity for 5-HT2A and 5-HT2C subtypes, but some of them displayed antagonistic activity in rat stomach fundus at micromolar concentrations.

New 2-pyridylethylamines with dopaminergic activity: Synthesis and radioligand-binding evaluation

Summary In order to determine whether the pyridine nucleus could replace the catechol moiety of the neurotransmitter dopamine or the phenol ring of the dopaminergic pharmacophore m-hydroxyphenylethylamine, the 2-(3-pyridyl)ethylamine 7, 2-(4-pyridyl)ethylamine 8, 2-(2-hydroxy-4-pyridyl)ethylamine 10 and their N,N-di-n-propyl and N-n-propyl-N-2-phenylethyl derivatives were synthesized. The affinities of the new compounds for D1 and D2 dopamine receptors were evaluated by displacement of [3H]SCH 23390 (D1 selective) and [3H]spiperone (D2 selective) on rat neostriatum sections. The 2-(4-pyridyl)ethylamine 8 and its N,N-di-n-propyl derivative 18 showed the same affinity for the D1 and D2 receptors. Other compounds bound to the D1 receptor with higher affinity than to the D2 receptor. The possibility that the above compounds act as agonists and antagonists at the dopamine D1 and D2 receptors is discussed on the basis of guanosine-5′-triphosphate and Na+ displacement curves.

Glycosyl and polyalcoholic prodrugs of lonidamine

Polyhydric alcohol derivatives of the anticancer agent lonidamine (LND) have been synthesized. The increased water solubility showed by prodrugs 4, 7, and 25 together with their logP values (2.19, 2.55, and 2.54, respectively) and chemical stability might be beneficial for prodrugs absorption after oral administration. Moreover, the new prodrugs undergo enzymatic hydrolysis in plasma and release LND demonstrating that they are promising candidates for in vivo investigations.

Synthesis and pharmacological properties of 2-azabicyclo[2.2.2]octane derivatives representing conformational restricted isopethidine analogues

Abstract The synthesis and preliminary pharmacological evaluation of the epimeric 2-methyl-6-phenyl-6-carbethoxy-2-azabicyclo[2.2.2]octanes, representing conformationally restricted isopethidine analogues, are reported.