<i>trans</i>-2,3-Dihydroxy-6a,7,8,12b-tetrahydro-6<i>H</i>-chromeno[3,4-<i>c</i>]isoquinoline: Synthesis, Resolution, and Preliminary Pharmacological Characterization of a New Dopamine D₁ Receptor Full Agonist

We report the synthesis of trans-2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno[3,4-c]isoquinoline hydrochloride 6 and the resolution of its enantiomers. This new compound is an oxygen bioisostere of the potent dopamine D1-selective full agonist dihydrexidine. The initial synthetic approach involved, as a key step, a Suzuki coupling between a chromene triflate and a boronate ester, followed by isoquinoline formation and reduction of the resulting isoquinoline. Subsequently, a more efficient route was developed that involved conjugate addition of an aryl Grignard reagent to a 2-nitrochromene. The title compound possessed high affinity (Ki = 20−30 nM) for porcine D1-like receptors in native striatal tissue and full intrinsic activity at cloned human dopamine D1 receptors but had much lower affinity at dopamine D2-like receptors (Ki = 3000 nM). The binding and functional properties of this compound illustrate again the utility of constructing dopamine D1 agonist ligands around the β-phenyldopamine pharmacophore template

<i>trans</i>-2,3-Dihydroxy-6a,7,8,12b-tetrahydro-6<i>H</i>-chromeno[3,4-<i>c</i>]isoquinoline: Synthesis, Resolution, and Preliminary Pharmacological Characterization of a New Dopamine D₁ Receptor Full Agonist

We report the synthesis of trans-2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno[3,4-c]isoquinoline hydrochloride 6 and the resolution of its enantiomers. This new compound is an oxygen bioisostere of the potent dopamine D1-selective full agonist dihydrexidine. The initial synthetic approach involved, as a key step, a Suzuki coupling between a chromene triflate and a boronate ester, followed by isoquinoline formation and reduction of the resulting isoquinoline. Subsequently, a more efficient route was developed that involved conjugate addition of an aryl Grignard reagent to a 2-nitrochromene. The title compound possessed high affinity (Ki = 20−30 nM) for porcine D1-like receptors in native striatal tissue and full intrinsic activity at cloned human dopamine D1 receptors but had much lower affinity at dopamine D2-like receptors (Ki = 3000 nM). The binding and functional properties of this compound illustrate again the utility of constructing dopamine D1 agonist ligands around the β-phenyldopamine pharmacophore template

Correlation among chemical structure, surface properties and cytotoxicity of N-acyl alanine and serine surfactants

Toxicity is one of the main concern limiting the use of surfactants. Many efforts have been devoted to the development of new amphiphilic molecules characterized by a lower toxicological profile and environmental impact. N-acyl amino acids are a class of anionic surfactants that can find applications in different technological fields as an alternative to sulphate-based surfactants (e.g., sodium dodecyl sulphate).The understanding of the relationship between chemical structure and toxicological profile is fundamental for the disclosure of the full potential of these amphiphiles. With this aim, two series of N-acyl surfactants, with different length of the hydrophobic tails and serine or alanine as polar head, were synthesized and fully characterized.The correlation between the surface and toxicological parameters allowed highlighting the role exerted by the length of the hydrocarbon chain and the polar head on cytotoxicity. The length of the hydrocarbon chain mainly influences surface properties and toxicological parameters, while the amino acid polar head plays a key role only on cellular toxicity. Overall, our data suggest that minor differences in the polar head, not affecting significantly CMC values, may have a strong impact on cytotoxicity.</p

Correlation among chemical structure, surface properties and cytotoxicity of N-acyl alanine and serine surfactants

Toxicity is one of the main concern limiting the use of surfactants. Many efforts have been devoted to the development of new amphiphilic molecules characterized by a lower toxicological profile and environmental impact. N-acyl amino acids are a class of anionic surfactants that can find applications in different technological fields as an alternative to sulphate-based surfactants (e.g., sodium dodecyl sulphate).The understanding of the relationship between chemical structure and toxicological profile is fundamental for the disclosure of the full potential of these amphiphiles. With this aim, two series of N-acyl surfactants, with different length of the hydrophobic tails and serine or alanine as polar head, were synthesized and fully characterized.The correlation between the surface and toxicological parameters allowed highlighting the role exerted by the length of the hydrocarbon chain and the polar head on cytotoxicity. The length of the hydrocarbon chain mainly influences surface properties and toxicological parameters, while the amino acid polar head plays a key role only on cellular toxicity. Overall, our data suggest that minor differences in the polar head, not affecting significantly CMC values, may have a strong impact on cytotoxicity.</p

Scaffold Hybridization Strategy Leads to the Discovery of Dopamine D₃ Receptor-Selective or Multitarget Bitopic Ligands Potentially Useful for Central Nervous System Disorders

In the search for novel bitopic compounds targeting the dopamine D3 receptor (D3R), the N-(2,3-dichlorophenyl)­piperazine nucleus (primary pharmacophore) has been linked to the 6,6- or 5,5-diphenyl-1,4-dioxane-2-carboxamide or the 1,4-benzodioxane-2-carboxamide scaffold (secondary pharmacophore) by an unsubstituted or 3-F-/3-OH-substituted butyl chain. This scaffold hybridization strategy led to the discovery of potent D3R-selective or multitarget ligands potentially useful for central nervous system disorders. In particular, the 6,6-diphenyl-1,4-dioxane derivative 3 showed a D3R-preferential profile, while an interesting multitarget behavior has been highlighted for the 5,5-diphenyl-1,4-dioxane and 1,4-benzodioxane derivatives 6 and 9, respectively, which displayed potent D2R antagonism, 5-HT1AR and D4R agonism, as well as potent D3R partial agonism. They also behaved as low-potency 5-HT2AR antagonists and 5-HT2CR partial agonists. Such a profile might be a promising starting point for the discovery of novel antipsychotic agents

Preparation and Pharmacological Characterization of <i>trans</i>-2-Amino-5(6)-fluoro-6(5)-hydroxy-1-phenyl-2,3-dihydro-1<i>H</i>-indenes as D₂-like Dopamine Receptor Agonists

The present work reports the synthesis of trans-2-amino-5(6)-fluoro-6(5)-hydroxy-1-phenyl-2,3-dihydro-1H-indenes (4a−f, 5a−f) as a continuation of our studies to better understand the significance of the halo substituent in the trans-1-phenyl-2-aminoindane series and to extend knowledge of the monophenolic ligands of DA receptors. The affinity of the new compounds and related methoxylated precursors (10−15 and 18−23) was estimated in vitro by displacement of [3H]SCH23390 (for D1-like receptors) or [3H]YM-09-151-2 (for D2-like receptors) from homogenates of porcine striatal membranes. The results indicate that unsubstituted amines 4a, 5a, 10, and 11 are poorly effective at DA receptors. The introduction of two n-propyl groups on the nitrogen atom (compounds 14, 15, 4c, and 5c) and N-allyl-N-methyl- or N-methyl-N-propyl- substitution (compounds 20−23, 4e, 4f, 5e, 5f) increased the D2-like affinities and selectivity. The D2-like agonistic activity of selected compounds 15, 20, 21, 4e, 5c, and 5e was proved by evaluating their effects on the cyclic guanosine monophosphate (cGMP) content in rat neostriatal membranes. All tested compounds displayed a potential dopamine D2-like agonist profile decreasing basal levels of cGMP. The selective D2-like agonism of compounds 20 and 5e was proved by their effects on basal striatal adenylyl cyclase activity

1‑[3-(4-Butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1) as a Model for the Rational Design of a Novel Class of Brain Penetrant Ligands with High Affinity and Selectivity for Dopamine D₄ Receptor

In the present article, the M₁ mAChR bitopic agonist 1-[3-(4-butylpiperidin-1-yl)­propyl]-1,2,3,4-tetrahydroquinolin-2-one (77-LH-28-1, <b>1</b>) has been demonstrated to show unexpected D₄R selectivity over D₂R and D₃R and to behave as a D₄R antagonist. To better understand the structural features required for the selective interaction with the D₄R and to obtain compounds unable to activate mAChRs, the aliphatic butyl chain and the piperidine nucleus of <b>1</b> were modified, affording compounds <b>2</b>–<b>14</b>. The 4-benzylpiperidine <b>9</b> and the 4-phenylpiperazine <b>12</b> showed high D₄R affinity and selectivity not only over the other D₂-like subtypes, but also over M₁–M₅ mAChRs. Derivative <b>12</b> was also highly selective over some selected off-targets. This compound showed biased behavior, potently and partially activating G_i protein and inhibiting β-arrestin2 recruitment in functional studies. Pharmacokinetic studies demonstrated that it was characterized by a relevant brain penetration. Therefore, <b>12</b> might be a useful tool to better clarify the role played by D₄R in disorders in which this subtype is involved

Highly Potent and Selective Dopamine D₄ Receptor Antagonists Potentially Useful for the Treatment of Glioblastoma

To better understand the role of dopamine D4 receptor (D4R) in glioblastoma (GBM), in the present paper, new ligands endowed with high affinity and selectivity for D4R were discovered starting from the brain penetrant and D4R selective lead compound 1-(3-(4-phenylpiperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one (6). In particular, the D4R antagonist 24, showing the highest affinity and selectivity over D2R and D3R within the series (D2/D4 = 8318, D3/D4 = 3715), and the biased ligand 29, partially activating D4R Gi-/Go-protein and blocking β-arrestin recruitment, emerged as the most interesting compounds. These compounds, evaluated for their GBM antitumor activity, induced a decreased viability of GBM cell lines and primary GBM stem cells (GSC#83), with the maximal efficacy being reached at a concentration of 10 μM. Interestingly, the treatment with both compounds 24 and 29 induced an increased effect in reducing the cell viability with respect to temozolomide, which is the first-choice chemotherapeutic drug in GBM