Gian Mario Cingolani

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.

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.

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.

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.

Indolizine derivatives with biological activity V. 1-(2-Aminoethyl)-2-methylindolizine and its N-alkyl derivatives

Abstract In continuing the search for new biologically active agents in the indolizine field, 1-(2-aminoethyl)-2-methylindolizine and some N -alkyl derivatives have been synthesized. Preliminary pharmacological evaluation showed that these compounds exhibited anti-acetylcholine, anti-histamine and central nervous system (CNS) depressant activities.

Synthesis and evaluation of 2-(5-methoxythiophen-3-yl)ethylamines as potential dopamine agonists

Abstract The synthesis of 2-(5-methoxythiophen-3-yl)ethylamine and some derivatives bearing propyl and 2-phenylethyl substituents on the amino group has been described. The affinities for dopamine D 1 and D 2 receptors were evaluated by binding assays on rat striatum. None of the compounds show affinity for the D 1 receptor. In the D 2 binding assays the N -propyl- N -(2-phenylethyl) derivatives show affinity similar to that of the reference compound N-n -propyl- N -(2-phenylethyl)-2-(3-hydroxyphenyl)ethylamine ( 1 , RU 24213). In preliminary behavioral tests [2-(5-methoxythiophen-3-yl)ethyl]phenethylpropylamine behaves as a selective D 2 agonist.

Synthesis and preliminary pharmacological evaluation of 5-hydroxy- and 5,6-dihydroxy-1,2,3,7,12,12a-hexahydrobenzo[5,6]cyclohepta[1,2,3-ij]isoquinoline derivatives as dopamine receptor ligands.

A series of 5-hydroxy- and 5,6-dihydroxy-1,2,3,7,12,12a-hexahydrobenzo[5,6]cyclohepta[1,2,3-ij]isoquinoline derivatives (5a--e and 6a--e) were synthesized as conformationally rigid analogues of 1-benzyltetrahydroisoquinoline and evaluated for their affinity at D(1) and D(2) dopamine receptors. All compounds showed lower D(1) and D(2) affinities than dopamine. The 5-hydroxy-1-methyl-2,3,12,12a-hexahydrobenzo[5,6]cyclohepta[1,2,3-ij]isoquinoline 5a and the 5,6-dihydroxy analogue 6a showed D(2) agonist activity. This was proved by their effects on prolactin release from primary cultures of rat anterior pituitary cells. Molecular modeling studies showed that the geometric parameters (namely the distances from meta and para hydroxyl oxygens to the nitrogen and the height of nitrogen from the hydroxylated phenyl ring plane) of the dopaminergic pharmacophore embedded in our compounds have lower values in comparison with those observed in D(1) and D(2) selective ligands.