Ugo Gulini

Doxazosin-related alpha1-adrenoceptor antagonists with prostate antitumor activity.

Doxazosin analogues 1-3 and 1a were synthesized and investigated at alpha1-adrenoceptors and PC-3, DU-145, and LNCaP human prostate cancer cells. Compound 1 (cyclodoxazosin) was a potent alpha(1B)-adrenoceptor antagonist displaying antiproliferative activity higher than that of doxazosin in cancer cells in vitro and in vivo, respectively. Because of its antitumor efficacy at low concentrations, lower apoptotic activity in NHDF vs tumor cells, and antiangiogenetic effect, 1 showed a better therapeutic profile relative to doxazosin.

Synthesis and Antimuscarinic Activity of Derivatives of 2-Substituted-1,3-Dioxolanes

Geometric cis, trans isomers, derivatives of 2-substituted-1,3-dioxolanes and 2-substituted-1,3-dioxanes were designed and studied as antimuscarinic agents. The synthesized compounds were evaluated as perchlorides and methiodides by functional tests with rabit vas deferens (putatvie M1), guinea-pig heart (M2) and guinea-pig ileum (M3). The effect of the replacement of a trimethylammonium group with a dimethylsulfonium in the two rings was also evalutated. Pharmacological results indicate that the 1,3-dioxane nucleus shows the highest stereoselective values on the studied receptors.

Synthesis, NMR spectroscopy study, and antimuscarinic activity of a series of 2-(Acyloxymethyl)-1,3-dioxolanes

A series of 1,3-dioxolane-based ligands, bearing hydroxymethyl or ester functionalities, was synthesized and tested as potential muscarinic antagonists. The compounds display moderate to low affinity for the three receptor subtypes M1-M3, with some of them showing a significant selectivity for the M3 subtype. The configurational and conformational properties were studied using NOE experiments and vicinal coupling constants. The 1H and 13C NMR chemical shifts show stereochemically dependent trends. Quantitative analysis of conformer populations showed that the exocyclic CH2N CH3)3 group is prevalently in a pseudo-axial orientation in the cis isomers and in a pseudo-equatorial orientation in the trans isomers.

α1-Adrenoreceptor antagonists bearing a quinazoline or a benzodioxane moiety

Publisher Summary This chapter focuses on α 1 -adrenoreceptor antagonists bearing a quinazoline or a benzodioxane moiety. Prazosin, the prototype of quinazoline-bearing compounds, is a selective α 1 -adrenoreceptor antagonist widely used as a pharmacological tool for α-adrenoreceptor subtypes characterization and as an effective agent in the management of hypertension. For these reasons, prazosin represents a valid tool to explore α1-adrenoreceptor binding site topography and a lead compound in developing new therapeutically useful agents. The role of piperazine ring of prazosin has been investigated through its replacement by an α,ω-alkanediamine chain. Benzodioxanes represent one of the oldest and best known classes of α-adrenoreceptor antagonists, whose chemical structure incorporates a 1,4-benzodioxan-2-yl moiety as the main feature. WB 4101 is the prototype of α1-adrenoreceptor antagonists bearing a benzodioxane moiety. Several investigations have been devoted to improving both affinity and selectivity.

Searching for cyclazosin analogues as α1B-adrenoceptor antagonists

Abstract A series of quinazoline derivatives, 2 – 20 , structurally related to the racemic α 1 -adrenoceptor antagonist cyclazosin ( 1 ), were synthesized and evaluated for their functional antagonism at α 1 - and α 2 -adrenoceptors and for their binding affinity at human cloned α 1a -, α 1b - and α 1d -adrenoceptor subtypes. They displayed, like 1 , preferential antagonism and selectivity for α 1 versus α 2 -adrenoceptors. Compounds 10 , 13 , and 18 showed high potency at α 1 -adrenoceptors similar to that of 1 (p K B values 8.47–8.89 versus 8.67), whereas 13 and 15 were endowed with the highest α 1 -adrenoceptor selectivity, only 3- to 4-fold lower than that of 1 . In binding experiments, all of the compounds displayed an affinity practically similar to that found for 1 , with the exception of 19 and 20 that were definitely less potent. The s -triazine analogue 18 was the most potent of the series with p K i values of 10.15 (α 1a ), 10.22 (α 1b ) and 10.40 (α 1d ), resulting 77-fold more potent than 1 at α 1a -adrenoceptors. In addition, the majority of compounds, like prototype 1 , showed the same trend of preferential affinity for α 1d - and α 1b -adrenoceptors that α 1a -subtype. In conclusion, we identified compounds 2 – 5 , 10 , 12 and 13 , bearing either an aliphatic- or an arylalkyl- or aryloxyalkyl-acyl function, with an interesting subtype-selectivity profile, which makes them suitable candidates for their resolution as enantiomers structurally related to (+)-cyclazosin.

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.

(+)-Cyclazosin Derivatives as α1-Adrenoceptor Antagonists

The prazosin-related compound (+)-cyclazosin [(+)-1] is an α 1 -adrenoceptor antagonist with moderate selectivity for the α 1 b -adrenoceptor subtype (selectivity ratio: α 1 b /α 1 a = 90, α 1 b /α 1 d = 24). To improve its pharmacological profile, the novel chiral derivatives (+)-2-(+)-5, bearing a bromo, a methyl, a methoxy or an acetyl group in position 5 of the 2-furoyl moiety, were synthesized and evaluated for their α 1 -adrenoceptor blocking activity. All the compounds displayed, like (+)-1, high and preferential affinity for the α 1 b -adrenoceptor in binding and functional assays. Interestingly, in functional assays, compounds (+)-3 and (+)-4 showed, in comparison with (+)-1, an increase in the α 1 B /α 1 A selectivity (407 and 724 vs. 44), whereas compound (+)-5 exhibited an improved α 1 B / α 1 D selectivity (1513 vs. 138).

Synthesis and α1-adrenoceptor antagonist activity of tamsulosin analogues.

Tamsulosin (-)-1 is the most utilized α(1)-adrenoceptor antagonist in the benign prostatic hyperplasia therapy owing to its uroselective antagonism and capability in relieving both obstructive and irritative lower urinary tract symptoms. Here we report the synthesis and pharmacological study of the homochiral (-)-1 analogues (-)-2-(-)-5, bearing definite modifications in the 2-substituted phenoxyethylamino group in order to evaluate their influence on the affinity profile for α(1)-adrenoceptor subtypes. The benzyl analogue (-)-3, displaying a preferential antagonist profile for α1A-than α1D-and α1B-adrenoceptors, and a 12-fold higher potency at α1A-adrenoceptors with respect to the α1B subtype, may have improved uroselectivity compared to (-)-1.

Structure–Activity relationships among novel phenoxybenzamine-Related β-Chloroethylamines

A series of b-chloroethylamines 5-18, structurallyrelated to the irreversible a1-adrenoceptor antagonist phenoxy- benzamine (PB, N-benzyl-N-(2-chloroethyl)-N-(1-methyl-2-phenoxyethyl)amine hydrochloride, 1) and the competitive antagonist WB4101 (N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-N-(2-(2,6-dimethoxyphenoxy)ethyl)amine hydrochloride, 2), were synthesized and evaluated for their activityat a-adrenoceptors of the epididymal and the prostatic portion of young CD rat vas deferens. All compounds displayed irreversible antagonist activity. Most of them showed similar antagonism at both a1- and a2-adrenoceptors, whereas compounds 13 and 18, lacking substituents on both the phenoxy group and the oxyamino carbon chain, displayed a moderate a1-adrenoceptor selectivity(10-35 times), which was comparable to that of PB. Compounds 14 and 15, belonging to the benzyl series and bearing, respectively, a 2-ethoxyphenoxy and a 2-i-propoxyphenoxy moiety, were the most potent a1-adreno- ceptor antagonists with an affinityvalue similar to that of PB (pIC 50 values of 7.17 and 7.06 versus 7.27). Interestingly, several compounds were able to distinguish two a1-adrenoceptor subtypes in the epididymal tissue, as revealed by the discontinuity of their inhibition curves. A mean ratio of 24:76 for these a1-adrenoceptors was determined from compounds 8-10, 12, and 15-17. Fur- thermore, compounds 9, 10, 12, 16a, and 16b showed higher affinitytowards the minor population of receptors, whereas com- pounds 8, 15, and 17 preferentiallyinhibited the major population of a1-adrenoceptors. In addition, selected pharmacological experiments demonstrated the complementaryantagonism of the two series of compounds and their different, preferential affinity for one of the two a1-adrenoceptor subtypes. In conclusion, we found b-chloroethylamines that demonstrate a multiplicity of a1-adrenoceptors in the epididymal portion of young CD rat vas deferens and, as a consequence, they are possible useful tools for a1-adrenoceptor characterization. # 2002 Elsevier Science Ltd. All rights reserved.

Selective blockade of muscarinic M2 receptors in vivo by the new antagonist tripitramine.

The antimuscarinic effects of tripitramine (1, 1, 24--tris [[5, 11-dihydro-6-oxo-6H-pyrido [2, 3-b][1, 4]-benzodiazepin-11-yl)(carbonyl] methyl]-8, 17-dimethyl-1, 8, 17, 24-tetraazatetracosane tetraoxalate), a member of a series of polymethylene tetraamines with in vitro cardioselectivity, were assessed in two in vivo preparations: anaesthetized and pithed rats. The well-known M2 selective antagonist methoctramine was used in a comparative study. Tripitramine (0.0202 μmol/kg i.v.) proved to be a potent antagonist at cardiac M2 receptors that mediate the decrease in heart rate in the pithed rat; the same dose of this antagonist in the anaesthetized rat did not significantly affect the depressor action of methacholine mediated by vascular M3 receptors. In the pithed rat, this dose did not affect the ganglionic M1 receptor-mediated tachycardia and pressor response to muscarme or McN-A-343. These in vivo data are consistent with the in vitro findings and confirm that tripitramine is a more potent and selective muscarinic M2 receptor antagonist than methoctramine.