Franco Vittorio

A new sigma ligand, (±)-PPCC, antagonizes kappa opioid receptor-mediated antinociceptive effect

The compound (1R,2S/1S,2R)-2-[4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl) cyclopropanecarboxylate [(+/-)-PPCC] is a ligand with high affinity for sigma (sigma) sites of which the selectivity towards several other receptor systems has been demonstrated. Given the existence of a relationship between the sigma system and the kappa opioid (KOP)-mediated analgesia, to characterize the pharmacological properties of (+/-)-PPCC we analyzed its influence on the analgesic effect of the systemic injected kappa agonist (-)-U-50,488H comparing the effects with those shown by (+)-pentazocine and BD1047. The results demonstrate that the systemic administration of (+/-)-PPCC (1 mg/kg s.c.) does not modify basal tail-flick latency. Pre-treatment with (+/-)-PPCC, at the same dose, significantly decreased the antinociceptive effect of (-)-U-50,488H, analogously to the sigma compounds used. This study confirms that (+/-)-PPCC plays the role of sigma agonist in this model and strengthens the hypothesis of the sigma receptor modulatory role on KOP-mediated analgesia.

Protective effects of benzisothiazolylamidines on IL-1β induced alterations in human articular chondrocyte metabolism

The in vitro effects on human articular chondrocytes were evaluated for a series of N-benzo[d]isothiazol-3-yl-amidines, bearing as pharmacophoric moiety the nonacidic isosteric nitrogen analogue of the carboxylic group. The aim was to verify their effectiveness in articular diseases, such as arthritis. Human chondrocytes were treated with IL-1β in the presence of a series of N-benzo[d]isothiazol-3-yl-amidines at a concentration of 100 μg/mL. After 120 h, the amount of glycosaminoglycans (GAGs), the production of nitric oxide (NO) and the inhibition of metalloproteinases (MMP-3) and prostaglandin (PGE2) were measured. Nitrite production induced by inflammatory IL-1β on cultured chondrocytes was inhibited by the N-benzo[d]isothiazol-3-yl-amidines tested, in particular by N-benzo[d]isothiazol-3-yl-benzamidine, which was the most active. Concerning the effects on GAGs, all the tested benzisothiazolylamidines, and in particular N-benzo[d]isothiazol-3-yl-acetamidine, prevented the depletion of proteoglycan induced by IL-1β. Inhibitory effects of the tested compounds on MMP-3 activity and on PGE2 production were also observed.

Synthesis and pharmacological evaluation of potent and enantioselective σ1 and σ2 ligands

Abstract In a previous study we found that substitutions of the (+)- cis - N -normetazocine nucleus of (+)- MPCB with 1-adamantanamine provide the compound (±)- 10 with high affinity and selectivity for σ receptors. Starting with this result we have synthesized a new series of eight 1-phenyl-2-cyclopropylmethylamines structurally related to (±)- 10 , and binding affinities, with respect to σ 1 , σ 2 , opioid and dopaminergic D 2 receptors, have been reported. All compounds showed a negligible opioid and dopaminergic affinity and high selectivity for σ receptors. Modifications on the amino moiety and methylcarboxyester group of 10 provide compounds with different σ 1 and σ 2 binding affinity and selectivity. Moreover, we have also synthesized the respective enantiomers of componds (±)- 10 and (±)- 18 in order to evaluate the enantioselectivity for σ 1 and σ 2 receptors. The binding data showed that carboxymethylester on the cyclopropane ring was more critical for enantioselectivity than the hydroxymethylenic group. In fact, the (−)- 10 enantiomer showed a preference for σ 1 whereas (+)- 10 showed a preference for σ 2 .

CCB, a novel specific κ opioid agonist, which discriminates between opioid and σ1 recognition sites

Abstract CCB, 6,11 -Dimethyl-1,2,3,4,5,6-hexahydro-3-{[2′-methoxycarbonyl-2′-(4-chlorophenyl) cyclopropyl]methyl}-2,6-methano-3-benzazocin-8-ol, displays specificity and very high affinity for κ opioid receptor types (K 1 = 0.41 ± 0.19 nM). In contrast to other κ opioid agonists, CCB is also selective with respect to σ 1 sites (K 1 = 1,050 ± 55 nM). CCB displays antinociceptive and sedative effects in the mouse comparable to those of U50,488H and morphine. Naltrexone fully antagonizes these effects. The sedative effects of CCB are blocked in mice pretreated with naltrexone or nor-BNI. CCB and U50,488H produce a superimposable diuresis in rats. Naltrexone and nor-BNI, both are effective in antagonizing the effect. CCB does not produce any stereotyped behavior or ataxia in the behavioral assay in doses up to 40 mg/kg s.c., These findings suggest that CCB might be a useful tool to investigate the physiological role of κ opioid receptors.

Specific κ opioid receptor agonists

Abstract The results of studies on the design of a heterocyclic scaffold for the dynorphin A pharmacophore and on structure–affinity relationships in the MPCB/CCB series are described. The representative ligands provide insights to binding modes of benzomorphan derivatives to the κ opioid receptor.

Synthesis and binding affinity of cis-(−)- and cis-(+)-N-ethyleneamino-N-nordeoxymetazocine and cis-(−)-N-normetazocine analogues at σ1, σ2 and κ opioid receptors

Abstract The synthesis of cis-(+)- and cis-(−)-N-ethyleneamino-N-nordeoxymetazocine and cis-(−)-N-normetazocine analogues is described and their affinities to σ1, σ2 and κ opioid receptors are evaluated. The cis-(+)-deoxy compounds displayed high σ/κ selectivity with nanomolar Ki values for σ1 receptors, whereas in the cis-(−)-N-normetazocine series the compound (−)-7b was found to bind with nanomolar affinity to the κ opioid receptor (Ki=21.5 nM). Compound (−)-7b showed good selectivity for the κ opioid receptor in comparison to the σ1 and σ2 sites and to the μ and δ opioid receptors. A correlation of the binding affinities between cis-(−)- and cis-(+)-N-deoxynormetazocine derivatives show that both isomers of the deoxy analogs have similar σ1 and σ2 binding profiles as the cis-(+)-N-normetazocine derivatives.

Bivalent opioid peptides synthesized from μ selective monomers display preferential selectivity for δ receptors

Abstract A series of dimeric opioid peptides derived from μ selective compounds was synthesized to investigate whether μ and δ receptors coexist as distinct recognition sites on the same receptor complex. Some compounds were several times more potent than the corresponding monomers in the MVD (mouse vas deferens) smooth muscle preparation, which is rich in δ receptors, but yet retaining substantial activity in the GPI (guinea pig ileum). It is suggested that δ receptors might differ from μ receptors in that they possess an additional accessory recognition site, to which could bind a particular amino acid residue present in the second halves of these bivalent ligands. This residue could play the role of “address” at δ opioid receptors.