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1.
Eur J Med Chem ; 176: 310-325, 2019 Aug 15.
Article En | MEDLINE | ID: mdl-31112892

A series of compounds generated by ring expansion/opening and molecular elongation/simplification of the 1,3-dioxolane scaffold were prepared and tested for binding affinity at 5-HT1AR and α1 adrenoceptors. The compounds with greater affinity were selected for further functional studies. N-((2,2-diphenyl-1,3-dioxan-5-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-ammonium hydrogen oxalate (12) emerged as highly potent full agonist at the 5-HT1AR (pKi 5-HT1A = 8.8; pD2 = 9.22, %Emax = 92). The pharmacokinetic data in rats showed that the orally administered 12 has a high biodistribution in the brain compartment. Thus, 12 was further investigated in-vivo, showing an anxiolytic and antidepressant effect. Moreover, in the formalin test, 12 was able to decrease the late response to the noxious stimulus, indicating a potential use in the treatment of chronic pain.


Analgesics/therapeutic use , Anti-Anxiety Agents/therapeutic use , Antidepressive Agents/therapeutic use , Dioxanes/therapeutic use , Neuroprotective Agents/therapeutic use , Serotonin 5-HT1 Receptor Agonists/therapeutic use , Analgesics/chemical synthesis , Analgesics/pharmacokinetics , Analgesics/toxicity , Animals , Anti-Anxiety Agents/chemical synthesis , Anti-Anxiety Agents/pharmacokinetics , Anti-Anxiety Agents/toxicity , Antidepressive Agents/chemical synthesis , Antidepressive Agents/pharmacokinetics , Antidepressive Agents/toxicity , Brain/metabolism , Dioxanes/chemical synthesis , Dioxanes/pharmacokinetics , Dioxanes/toxicity , Male , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/pharmacokinetics , Neuroprotective Agents/toxicity , Rats, Sprague-Dawley , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, Adrenergic, alpha-1/metabolism , Serotonin 5-HT1 Receptor Agonists/chemical synthesis , Serotonin 5-HT1 Receptor Agonists/pharmacokinetics , Serotonin 5-HT1 Receptor Agonists/toxicity , Stereoisomerism , Structure-Activity Relationship
2.
Eur J Med Chem ; 168: 461-473, 2019 Apr 15.
Article En | MEDLINE | ID: mdl-30844609

A series of derivatives obtained by moving the aromatic moiety on the 1,4-dioxane ring of compounds 1-3 from position 6 to position 2 or 3 was prepared and evaluated for the affinity for 5-HT1A receptor (5-HT1AR) and α1-adrenoceptor (α1-AR) subtypes. Moreover, the flexible 2-ethanolamine linker of the most interesting compounds was replaced by the more conformationally constrained piperazine ring. In vitro functional studies performed on derivatives showing the highest affinities for 5-HT1AR highlighted that the shifting of the diphenyl moiety of derivatives 2 and 13 from position 6 to position 3 of the 1,4-dioxane nucleus, affording 11 and 16, respectively, modulated the 5-HT1AR functional profile from agonism to antagonism. Docking simulations, performed on the human 5-HT1AR, further rationalized the biological results, delving into the features which modulate the shift between agonist and antagonist activity. Interestingly, compound 11, endowed with mixed 5-HT1AR/α1d-AR antagonist profile, showed antiproliferative and cytotoxic effects on both PC-3 and DU-145 prostate cancer cell lines higher than those of the α1d-AR antagonist 2 and the 5-HT1AR antagonist 16. The experiments performed in the presence of the endogenous agonists norepinephrine and serotonin confirmed the involvement of both receptor systems in the antitumor activity of 11.


Antineoplastic Agents/pharmacology , Dioxanes/pharmacology , Prostatic Neoplasms/drug therapy , Receptor, Serotonin, 5-HT1A/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dioxanes/chemical synthesis , Dioxanes/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Male , Models, Molecular , Molecular Structure , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Structure-Activity Relationship
3.
ACS Chem Neurosci ; 10(5): 2222-2228, 2019 05 15.
Article En | MEDLINE | ID: mdl-30609891

The effect of methoxy and hydroxy substitutions in different positions of the phenoxy moiety of the N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-phenoxyethan-1-amine scaffold on the affinity/activity for D2-like, 5-HT1A, and α1-adrenoceptor subtypes was evaluated. Multitarget compounds with suitable combinations of dopaminergic and serotoninergic profiles were discovered. In particular, the 2-methoxy derivative 3 showed a multitarget combination of 5-HT1A/D4 agonism and D2/D3/5-HT2A antagonism, which may be a favorable profile for the treatment of schizophrenia. Interestingly, the 3-hydroxy derivative 8 behaved as a partial agonist at D2 and as a potent full agonist at D3 and D4 subtypes. In addition to its potent 5-HT1A receptor agonism, such a dopaminergic profile makes 8 a potential multitarget compound for the treatment of Parkinson's disease (PD). Indeed, the activation of 5-HT1A receptors might be helpful in reducing dyskinetic side effects associated with dopaminergic stimulation.


Antipsychotic Agents/therapeutic use , Dopamine D2 Receptor Antagonists/therapeutic use , Receptors, Dopamine D4/agonists , Schizophrenia/drug therapy , Serotonin 5-HT1 Receptor Agonists/therapeutic use , Serotonin 5-HT2 Receptor Antagonists/therapeutic use , Animals , Antipsychotic Agents/pharmacology , Dopamine D2 Receptor Antagonists/pharmacology , Drug Discovery , Humans , Serotonin 5-HT1 Receptor Agonists/pharmacology , Serotonin 5-HT2 Receptor Antagonists/pharmacology , Structure-Activity Relationship
4.
Future Med Chem ; 10(18): 2137-2154, 2018 Sep 01.
Article En | MEDLINE | ID: mdl-30043643

AIM: Targeting 5-HT1A receptor (5-HT1AR) as a strategy for CNS disorders and pain control. METHODOLOGY: A series of 1,3-dioxolane-based 2-heteroaryl-phenoxyethylamines was synthesized by a convergent approach and evaluated at α1-adrenoceptors and 5-HT1AR by binding and functional experiments. Absorption, distribution, metabolism, excretion and toxicity prediction studies were performed to explore the drug-likeness of the compounds. RESULTS & CONCLUSION: The most promising compound, the pyridin-4-yl derivative, emerged as a potent and selective 5-HT1AR agonist (pKi = 9.2; pD2 = 8.83; 5-HT1A/α1 = 135). In vitro it was able to permeate by passive diffusion MDCKII-MDR1 monolayer mimicking the blood-brain barrier and showed promising neuroprotective activity.


Central Nervous System Diseases/drug therapy , Dioxolanes/chemistry , Dioxolanes/pharmacology , Neuralgia/drug therapy , Neuroprotective Agents/pharmacology , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin Receptor Agonists/chemical synthesis , Serotonin Receptor Agonists/pharmacology , Central Nervous System Diseases/metabolism , Dioxolanes/chemical synthesis , Dose-Response Relationship, Drug , Humans , Molecular Structure , Neuralgia/metabolism , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Serotonin Receptor Agonists/chemistry , Structure-Activity Relationship
5.
ChemMedChem ; 12(22): 1893-1905, 2017 11 22.
Article En | MEDLINE | ID: mdl-28940806

A new series of spirocyclic σ receptor (σR) ligands were prepared and studied. Most were found to have a high affinity and selectivity for σ1 R; three compounds were shown to be σ1 R agonists, while another proved to be the only σ1 R antagonist. Only one of the σ1 R agonists (BS148) also exhibited σ2 R selectivity and was able to inhibit the growth of metastatic malignant melanoma cell lines without affecting normal human melanocytes. The antiproliferative activity of this compound suggested an σ2 R agonist profile. Further, preliminary investigations indicated that the mechanism of metastatic malignant melanoma cell death induced by BS148 is due, at least in part, to apoptosis.


Analgesics, Opioid/pharmacology , Antineoplastic Agents/pharmacology , Melanoma/drug therapy , Piperidines/pharmacology , Receptors, sigma/agonists , Spiro Compounds/pharmacology , Analgesics, Opioid/chemical synthesis , Analgesics, Opioid/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Death/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Cells, Cultured , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Ligands , Male , Melanoma/pathology , Mice , Models, Molecular , Molecular Structure , Piperidines/chemical synthesis , Piperidines/chemistry , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Structure-Activity Relationship
6.
Eur J Med Chem ; 136: 259-269, 2017 Aug 18.
Article En | MEDLINE | ID: mdl-28499171

New α1-adrenoreceptor (α1-AR) antagonists related to prazosin and doxazosin were synthesized by replacing piperazine ring with (S)- or (R)-3-aminopiperidine. Binding studies indicated that the S configuration at the 3-C position of the piperidine ring is crucial for an optimal interaction of the compounds at all three α1-AR subtypes. Quinazolines 9 and 10, bearing a quinone ring on the lateral chain, exhibited also potent antiproliferative activity in LNCaP androgen-sensitive prostate cancer cell lines, higher than that of doxazosin. Compound 10 increased apoptosis, in terms of DNA fragmentation, without triggering cell necrosis. The prooxidant activity found in compound 10 may underlie its ability to inhibit cell proliferation in synergy with the effect mediated by α1-AR antagonism. Due to its better biological profile compared to doxazosin for LNCaP cell line, compound 10 might be a valuable lead compound for the design of new prostate antitumor agents.


Adrenergic alpha-1 Receptor Antagonists/pharmacology , Prostatic Neoplasms/drug therapy , Quinazolines/pharmacology , Receptors, Adrenergic, alpha-1/metabolism , Adrenergic alpha-1 Receptor Antagonists/chemical synthesis , Adrenergic alpha-1 Receptor Antagonists/chemistry , Apoptosis/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Male , Molecular Structure , Prostatic Neoplasms/pathology , Quinazolines/chemical synthesis , Quinazolines/chemistry , Structure-Activity Relationship , Tumor Cells, Cultured
7.
Eur J Med Chem ; 125: 435-452, 2017 Jan 05.
Article En | MEDLINE | ID: mdl-27689727

Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a potent 5-HT1AR agonist with a moderate 5-HT1AR selectivity. In an extension of this work a series of derivatives of 1, obtained by combining different heterocyclic rings with a more flexible amine chain, was synthesized and tested for binding affinity and activity at 5-HT1AR and α1 adrenoceptors. The results led to the identification of 14 and 15 as novel 5-HT1AR partial agonists, the first being outstanding for selectivity (5-HT1A/α1d = 80), the latter for potency (pD2 = 9.58) and efficacy (Emax = 74%). Theoretical studies of ADME properties shows a good profile for the entire series and MDCKII-MDR1 cells permeability data predict a good BBB permeability of compound 15, which possess a promising neuroprotective activity. Furthermore, in mouse formalin test, compound 15 shows a potent antinociceptive activity suggesting a new strategy for pain control.


Alkanes/chemistry , Alkanes/therapeutic use , Analgesics/chemistry , Analgesics/therapeutic use , Pain/drug therapy , Serotonin 5-HT1 Receptor Agonists/chemistry , Serotonin 5-HT1 Receptor Agonists/therapeutic use , Alkanes/pharmacokinetics , Alkanes/pharmacology , Analgesics/pharmacokinetics , Analgesics/pharmacology , Animals , Blood-Brain Barrier/metabolism , Formaldehyde , Humans , Male , Mice , Models, Molecular , Pain/chemically induced , Pain Measurement , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin 5-HT1 Receptor Agonists/pharmacokinetics , Serotonin 5-HT1 Receptor Agonists/pharmacology , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity Relationship
8.
Eur J Med Chem ; 125: 233-244, 2017 Jan 05.
Article En | MEDLINE | ID: mdl-27662034

N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-(2-methoxyphenoxy)ethan-1-amine (3) is a potent 5-HT1A receptor and α1d-adrenoceptor (α1d-AR) ligand. Analogues 5-10 were rationally designed and prepared to evaluate whether electronic and/or lipophilic properties of substituents in the ortho position of its phenoxy moiety exert any favorable effects on the affinity/activity at 5-HT1A receptor and improve selectivity over α1-ARs. To rationalize the experimental observations and derive information about receptor-ligand interactions of the reported ligands, docking studies, using 5-HT1A and α1d-AR models generated by homology techniques, and a retrospective computational study were performed. The results highlighted that proper substituents in position 2 of the phenoxy moiety of 3 selectively address the ligands toward 5-HT1A receptor with respect to α1-ARs and D2-like receptor subtypes. Methoxymethylenoxy derivative 9 showed the best 5-HT1A selectivity profile and the highest potency at 5-HT1A receptor, behaving as a partial agonist. Finally, 9, tested in light/dark exploration test in mice, significantly reduced anxiety-linked behaviors. Therefore, it may be considered a lead for the design of partial agonists potentially useful in the treatment of disorders in which 5-HT1A receptor is involved.


Amines/metabolism , Dioxanes/metabolism , Ethylamines/metabolism , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, Adrenergic, alpha-1/metabolism , Animals , Anti-Anxiety Agents/chemistry , Anti-Anxiety Agents/pharmacology , Anxiety/drug therapy , Ligands , Mice , Molecular Docking Simulation , Receptor, Serotonin, 5-HT1A/drug effects , Receptors, Adrenergic, alpha-1/drug effects , Retrospective Studies , Structure-Activity Relationship
9.
ChemMedChem ; 11(20): 2287-2298, 2016 10 19.
Article En | MEDLINE | ID: mdl-27690321

The involvement of the serotonin 5-HT1A receptor (5-HT1A -R) in the antidepressant effect of allyphenyline and its analogues indicates that ligands bearing the 2-substituted imidazoline nucleus as a structural motif interact with 5-HT1A -R. Therefore, we examined the 5-HT1A -R profile of several imidazoline molecules endowed with a common scaffold consisting of an aromatic moiety linked to the 2-position of an imidazoline nucleus by a biatomic bridge. Our aim was to discover other ligands targeting 5-HT1A -R and to identify the structural features favoring 5-HT1A -R interaction. Structure-activity relationships, supported by modeling studies, suggested that some structural cliché such as a polar function and a methyl group in the bridge, as well as proper steric hindrance in the aromatic area of the above scaffold, favored 5-HT1A -R recognition and activation. We also highlighted the potent antidepressant-like effect (mouse forced swimming test) of (S)-(+)-19 [(S)-(+)-naphtyline] at very low dose (0.01 mg kg-1 ). This effect was clearly mediated by 5-HT1A , as it was significantly reduced by pretreatment with the 5-HT1A antagonist WAY100635.


Imidazolines/pharmacology , Receptor, Serotonin, 5-HT1A/metabolism , Serotonin 5-HT1 Receptor Antagonists/pharmacology , Dose-Response Relationship, Drug , Humans , Imidazolines/chemical synthesis , Imidazolines/chemistry , Ligands , Molecular Structure , Serotonin 5-HT1 Receptor Antagonists/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists/chemistry , Structure-Activity Relationship
10.
Eur J Med Chem ; 122: 601-610, 2016 Oct 21.
Article En | MEDLINE | ID: mdl-27448917

Arylpiperazines 2-11 were synthesized, and their biological profiles at α1-adrenergic receptors (α1-ARs) assessed by binding assays in CHO cells expressing human cloned subtypes and by functional experiments in isolated rat vas deferens (α1A), spleen (α1B), and aorta (α1D). Modifications at the 1,3-benzodioxole and phenyl phamacophoric units resulted in the identification of a number of potent compounds (moderately selective with respect to the α1b-AR), in binding experiments. Notably, compound 7 (LDT451) showed a subnanomolar pKi of 9.41 towards α1a-AR. An encouragingly lower α1B-potency was a general trend for all the series of compounds, which showed α1A/D over α1B selectivity in functional assays. If adequately optimized, such peculiar selectivity could have relevance for a potential LUTS/BPH therapeutic application.


Adrenergic alpha-1 Receptor Antagonists/chemical synthesis , Adrenergic alpha-1 Receptor Antagonists/pharmacology , Drug Design , Piperazines/chemical synthesis , Piperazines/pharmacology , Receptors, Adrenergic, alpha-1/metabolism , Adrenergic alpha-1 Receptor Antagonists/chemistry , Adrenergic alpha-1 Receptor Antagonists/metabolism , Animals , CHO Cells , Cell Line, Tumor , Chemistry Techniques, Synthetic , Cloning, Molecular , Cricetinae , Cricetulus , Humans , Male , Molecular Docking Simulation , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/drug effects , Piperazines/chemistry , Piperazines/metabolism , Protein Conformation , Rats , Receptors, Adrenergic, alpha-1/chemistry , Receptors, Adrenergic, alpha-1/genetics , Signal Transduction/drug effects , Structure-Activity Relationship
11.
Eur J Med Chem ; 112: 1-19, 2016 Apr 13.
Article En | MEDLINE | ID: mdl-26874044

Herein we report the synthesis and biological activity of new sigma receptor (σR) ligands obtained by combining different substituted five-membered heterocyclic rings with appropriate σR pharmacophoric amines. Radioligand binding assay, performed on guinea pig brain membranes, identified 25b (1-(1,4-dioxaspiro[4.5]decan-2-ylmethyl)-4-benzylpiperazine) as the most interesting compound of the series, displaying high affinity and selectivity for σ1R (pKiσ1 = 9.13; σ1/σ2 = 47). The ability of 25b to modulate the analgesic effect of the κ agonist (-)-U-50,488H and µ agonist morphine was evaluated in vivo by radiant heat tail-flick test. It exhibited anti-opioid effects on both κ and µ receptor-mediated analgesia, suggesting an agonistic behavior at σ1R. Docking studies were performed on the theoretical σ1R homology model. The present work represents a new starting point for the design of more potent and selective σ1R ligands.


Analgesics, Opioid/chemistry , Analgesics, Opioid/pharmacology , Dioxolanes/chemistry , Dioxolanes/pharmacology , Pain/drug therapy , Receptors, sigma/metabolism , Analgesics, Opioid/therapeutic use , Animals , Brain/drug effects , Brain/metabolism , Dioxolanes/therapeutic use , Guinea Pigs , Humans , Ligands , Models, Molecular , Molecular Docking Simulation , Morphine/pharmacology , Morphine/therapeutic use , Pain/metabolism , Rats , Receptors, Opioid, kappa/metabolism , Receptors, Opioid, mu/metabolism , Structure-Activity Relationship
12.
Bioorg Med Chem ; 23(13): 3040-58, 2015 Jul 01.
Article En | MEDLINE | ID: mdl-26014480

Metabotropic glutamate receptor 5 (mGlu5) is a biological target implicated in major neurological and psychiatric disorders. In the present study, we have investigated structural determinants of the interaction of negative allosteric modulators (NAMs) with the seven-transmembrane (7TM) domain of mGlu5. A homology model of the 7TM receptor domain built on the crystal structure of the mGlu1 template was obtained, and the binding modes of known NAMs, namely MPEP and fenobam, were investigated by docking and molecular dynamics simulations. The results were validated by comparison with mutagenesis data available in the literature for these two ligands, and subsequently corroborated by the recently described mGlu5 crystal structure. Moreover, a new series of NAMs was synthesized and tested, providing compounds with nanomolar affinity. Several structural modifications were sequentially introduced with the aim of identifying structural features important for receptor binding. The synthesized NAMs were docked in the validated homology model and binding modes were used to interpret and discuss structure-activity relationships within this new series of compounds. Finally, the models of the interaction of NAMs with mGlu5 were extended to include important non-aryl alkyne mGlu5 NAMs taken from the literature. Overall, the results provide useful insights into the molecular interaction of negative allosteric modulators with mGlu5 and may facilitate the design of new modulators for this class of receptors.


Antipsychotic Agents/chemical synthesis , Imidazoles/chemistry , Pyridines/chemistry , Receptor, Metabotropic Glutamate 5/antagonists & inhibitors , Allosteric Regulation , Allosteric Site , Antipsychotic Agents/chemistry , Drug Discovery , Humans , Kinetics , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding , Protein Structure, Tertiary , Receptor, Metabotropic Glutamate 5/chemistry , Receptors, Metabotropic Glutamate/chemistry , Structural Homology, Protein , Structure-Activity Relationship
13.
Eur J Med Chem ; 87: 248-66, 2014 Nov 24.
Article En | MEDLINE | ID: mdl-25261823

Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a highly selective and potent 5-HT1AR ligand. In the present work we adopted an in-parallel synthetic strategy to rapidly explore a new set of arylpiperazine (7-32) that is structurally related to 1. The compounds were tested for binding affinity and functional activity at 5-HT1AR and α1-adrenoceptor subtypes and SAR studies were drawn. In particular, compounds 9, 27 and 30 emerged as promising α1 receptor antagonists, while compound 10 behaves as the most potent and efficacious 5-HT1AR agonist. All the compounds were docked into the 5HT1AR theoretical model and the results were in agreement with the biological experimental data. These findings may represent a new starting point for developing more selective α1 or 5-HT1AR ligands.


Alkanes/chemistry , Alkanes/metabolism , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, Adrenergic, alpha-1/metabolism , Spiro Compounds/chemistry , Humans , Ligands , Molecular Docking Simulation , Protein Conformation , Receptor, Serotonin, 5-HT1A/chemistry , Receptors, Adrenergic, alpha-1/chemistry , Structure-Activity Relationship
14.
J Med Chem ; 55(1): 23-36, 2012 Jan 12.
Article En | MEDLINE | ID: mdl-22145629

A series of aralkylphenoxyethylamine and aralkylmethoxyphenylpiperazine compounds was synthesized and their in vitro pharmacological profile at both 5-HT(1A) receptors and α(1)-adrenoceptor subtypes was measured by binding assay and functional studies. The results showed that the replacement of the 1,3-dioxolane ring by a tetrahydrofuran, cyclopentanone, or cyclopentanol moiety leads to an overall reduction of in vitro affinity at the α(1)-adrenoceptor while both potency and efficacy were increased at the 5-HT(1A) receptor. A significant improvement of 5-HT(1A)/α(1) selectivity was observed in some of the cyclopentanol derivatives synthesized (4acis, 4ccis and trans). Compounds 2a and 4ccis emerged as novel and interesting 5-HT(1A) receptor antagonist (pK(i) = 8.70) and a 5-HT(1A) receptor partial agonist (pK(i) = 9.25, pD(2) = 9.03, E(max) = 47%, 5-HT(1A)/α(1a) = 69), respectively. Docking studies were performed at support of the biological data and to elucidate the molecular basis for 5-HT(1A) agonism/antagonism activity.


Cyclopentanes/chemical synthesis , Furans/chemical synthesis , Piperazines/chemical synthesis , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, Adrenergic, alpha-1/metabolism , Serotonin 5-HT1 Receptor Agonists/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists/chemical synthesis , Animals , Aorta, Thoracic/drug effects , Aorta, Thoracic/physiology , Binding Sites , CHO Cells , Cricetinae , Cricetulus , Cyclopentanes/chemistry , Cyclopentanes/pharmacology , Drug Partial Agonism , Furans/chemistry , Furans/pharmacology , HeLa Cells , Humans , In Vitro Techniques , Ligands , Male , Models, Molecular , Piperazines/chemistry , Piperazines/pharmacology , Radioligand Assay , Rats , Serotonin 5-HT1 Receptor Agonists/chemistry , Serotonin 5-HT1 Receptor Agonists/pharmacology , Serotonin 5-HT1 Receptor Antagonists/chemistry , Serotonin 5-HT1 Receptor Antagonists/pharmacology , Spleen/drug effects , Spleen/physiology , Stereoisomerism , Structure-Activity Relationship , Vas Deferens/drug effects , Vas Deferens/physiology
15.
Eur J Med Chem ; 45(9): 3740-51, 2010 Sep.
Article En | MEDLINE | ID: mdl-20605276

A series of 1,3-dioxolane-based compounds incorporating a lactam (2-4) or imide (5-7) moiety was synthesized and the pharmacological profile at alpha(1)-adrenoceptor subtypes and 5-HT(1A) receptor was assessed through binding and functional experiments. Starting from the 2,2-diphenyl-1,3-dioxolane derivative 1, previously shown to be a selective alpha(1a(A))/alpha(1d(D))-adrenoceptor subtype antagonist, over alpha(1b(B)) subtype and 5-HT(1A) receptor, and replacing one phenyl ring with lactam or imide moiety a reduction of alpha(1)/5-HT(1A) selectivity is observed, mainly due to the increase in 5-HT(1A) affinity. In functional experiments lactam derivatives seems to favour 5-HT(1A) receptor antagonism (pKb = 7.20-7.80) and alpha(1B)-adrenoceptor antagonist selectivity (alpha(1B)/alpha(1A) and alpha(1B)/alpha(1D) of about 10-fold). The most interesting of the various imide derivatives is compound 7t, which is a selective alpha(1D)-adrenoceptor antagonist (pKb = 8.1 and alpha(1D)/alpha(1A) and alpha(1D)/alpha(1B) selectivity ratios of 16 and 11 respectively) whereas at 5-HT(1A) receptor it is a potent partial agonist (pD2 = 7.98, E(max) = 60%).]. Given that cis and trans diastereomer pairs for 2-7 are possible, a computational strategy based on molecular docking studies was used to elucidate the atomic details of the 5HT(1A)/agonist and 5HT(1A)/antagonist interaction.


Dioxolanes/chemistry , Dioxolanes/metabolism , Imides/chemistry , Lactams/chemistry , Receptor, Serotonin, 5-HT1A/metabolism , Receptors, Adrenergic, alpha-1/metabolism , Adrenergic alpha-1 Receptor Agonists/chemical synthesis , Adrenergic alpha-1 Receptor Agonists/chemistry , Adrenergic alpha-1 Receptor Agonists/metabolism , Adrenergic alpha-1 Receptor Agonists/pharmacology , Adrenergic alpha-1 Receptor Antagonists/chemical synthesis , Adrenergic alpha-1 Receptor Antagonists/chemistry , Adrenergic alpha-1 Receptor Antagonists/metabolism , Adrenergic alpha-1 Receptor Antagonists/pharmacology , Animals , Dioxolanes/chemical synthesis , Dioxolanes/pharmacology , Humans , Ligands , Male , Models, Molecular , Protein Binding , Protein Conformation , Rats , Receptor, Serotonin, 5-HT1A/chemistry , Receptors, Adrenergic, alpha-1/chemistry , Serotonin 5-HT1 Receptor Agonists/chemical synthesis , Serotonin 5-HT1 Receptor Agonists/chemistry , Serotonin 5-HT1 Receptor Agonists/metabolism , Serotonin 5-HT1 Receptor Agonists/pharmacology , Serotonin 5-HT1 Receptor Antagonists/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists/chemistry , Serotonin 5-HT1 Receptor Antagonists/metabolism , Serotonin 5-HT1 Receptor Antagonists/pharmacology , Stereoisomerism , Structure-Activity Relationship , Substrate Specificity
16.
Bioorg Med Chem Lett ; 20(6): 2017-20, 2010 Mar 15.
Article En | MEDLINE | ID: mdl-20185311

Starting from compounds previously identified as alpha(1)-adrenoceptor antagonists that were also found to bind to the 5-HT(1A) receptor, in an attempt to separate the two activities, a new series of 5-HT(1A) receptor agonists was identified and shown to have high potency and/or high selectivity. Of these, compound 13, which combines high selectivity (5-HT(1A)/alpha(1)=151) and good agonist potency (pD(2)=7.82; E(max)=76), was found to be the most interesting.


Serotonin 5-HT1 Receptor Agonists , Drug Discovery
17.
ChemMedChem ; 4(2): 196-203, 2009 Feb.
Article En | MEDLINE | ID: mdl-19101959

Starting from compound 1, a previously reported alpha(1D)-adrenoceptors antagonist, a new series of ligands acting at 5-HT(1A) serotonin receptor were identified through simple structure modifications. Among them (2,2-diphenyl-[1,3]oxathiolan-5-yl-methyl)-(3-phenyl-propyl)amine (19) exhibits outstanding activity (pK(i)=8.72, pD(2)=7.67, E(max)=85) and selectivity (5-HT(1A)/alpha(1D)>150), and represents an as yet unidentified 5-HT(1A) agonist scaffold.


Heterocyclic Compounds, 1-Ring/pharmacology , Serotonin 5-HT1 Receptor Agonists , Serotonin Receptor Agonists/pharmacology , Animals , Aorta/drug effects , HeLa Cells , Heterocyclic Compounds, 1-Ring/chemistry , Humans , Magnetic Resonance Spectroscopy , Male , Prostate/drug effects , Radioligand Assay , Rats , Rats, Wistar , Serotonin Receptor Agonists/chemistry , Spleen/drug effects , Structure-Activity Relationship , Vas Deferens/drug effects
18.
Bioorg Med Chem Lett ; 19(3): 854-9, 2009 Feb 01.
Article En | MEDLINE | ID: mdl-19097783

The four stereoisomers of 2-oxazolidinone 5-substituted with 1-methyl-2-pyrrolidinyl (1), of 1,4-benzodioxane 2-substituted with the same residue (2) and of the nor-methyl analogue of this latter (2a) were synthesized as candidate nicotinoids. Of the 12 compounds, two N-methylated pyrrolidinyl-benzodioxane stereoisomers, namely those with the same relative configuration at the pyrrolidine stereocentre as (S)-nicotine, bind at alpha4beta2 nicotinic acetylcholine receptor with submicromolar affinity. Consistently with the biological data, docking analysis enlightens significant differences in binding site interactions not only between 1 and 2, but also between 2 and 2a and between the stereoisomers of 2 accounting for the critical role played, in the case of the pyrrolidinyl-benzodioxanes, by the chirality of both the stereolabile and stereostable stereogenic atoms, namely the protonated tertiary nitrogen and the two asymmetric carbons.


Dioxanes/chemical synthesis , Oxazolidinones/chemical synthesis , Pyrrolidines/chemical synthesis , Receptors, Nicotinic/chemistry , Acetylcholine/chemistry , Animals , Binding Sites , Brain/metabolism , Carbon/chemistry , Dioxanes/pharmacology , Hydrogen Bonding , Kinetics , Ligands , Models, Chemical , Oxazolidinones/pharmacology , Rats , Receptors, Nicotinic/metabolism , Stereoisomerism
19.
Bioorg Med Chem Lett ; 16(21): 5610-5, 2006 Nov 01.
Article En | MEDLINE | ID: mdl-16942873

The RS and SR enantiomers of 2-oxazolidinone and 1,4-benzodioxane bearing a 2-pyrrolidinyl substituent at the 5- and 2-position, respectively, were synthesized as candidate nicotinoids. One of the two benzodioxane stereoisomers reasonably fits the pharmacophore elements of (S)-nicotine and binds at alpha4beta2 nicotinic acetylcholine receptor with submicromolar affinity. Interestingly, both the synthesized pyrrolidinylbenzodioxanes exhibit analogous affinity at alpha(2) adrenergic receptor resembling the behaviour of some known alpha(2)-AR ligands recently proved to possess neuronal nicotinic affinity.


Dioxanes/chemical synthesis , Dioxanes/metabolism , Oxazolidinones/chemical synthesis , Oxazolidinones/metabolism , Receptors, Nicotinic/metabolism , Protein Binding
20.
J Pharmacol Exp Ther ; 315(1): 109-17, 2005 Oct.
Article En | MEDLINE | ID: mdl-15951403

The pharmacological properties of cyclohexanecarboxylic acid, {2-[4-(2-bromo-5-methoxybenzyl)piperazin-1-yl]ethyl}-(2-trifluoromethoxyphenyl)amide (Rec 27/0224), and cyclohexanecarboxylic acid, (2-methoxy-phenyl)-{2-[4-(2-methoxyphenyl)-piperazin-1-yl]ethyl}amide (Rec 27/0074), were characterized using radioligand displacement and guanosine 5'-O-(3-[35S]thiotriphosphate) ([35S]GTPgammaS) binding assays, as well as electrophysiological experiments, in rat hippocampal and dorsal raphe nucleus (DRN) slices. Both compounds showed a high affinity (Ki, approximately 1 nM) and selectivity (>70-fold) at human 5-hydroxytryptamine (5-HT)1A receptors versus other 5-HT receptors. In [35S]GTPgammaS binding assays on HeLa cells stably expressing human 5-HT1A receptors, Rec 27/0224 and Rec 27/0074 inhibited basal [35S]GTPgammaS binding by 44.8 +/- 1.7% (pEC50 = 8.58) and 25 +/- 2.5% (pEC50 = 8.86), respectively. In intracellularly recorded CA1 pyramidal cells, 5-HT1A (hetero)receptor-mediated hyperpolarization, elicited by 100 nM 5-carboxamidoytryptamine (5-CT), was partially antagonized by Rec 27/0224 (approximately 50%; IC50 = 18.0 nM) and Rec 27/0074 (74%; IC50 = 0.8 nM). In extracellularly recorded DRN serotonergic neurons, Rec 27/0224 and Rec 27/0074 fully antagonized the inhibition of firing caused by the activation of 5-HT1A (auto)receptors by 30 nM 5-CT with an IC50 of 34.9 nM and 16.5 nM, respectively. The antagonism had a slow time course, reaching a steady state within 60 min. Both compounds also antagonized the citalopram-elicited, endogenous 5-HT-mediated inhibition of cell firing. In conclusion, Rec 27/0224 and Rec 27/0074 exhibited inverse agonism in [35S]GTPgammaS binding assays and differential antagonistic properties on 5-HT1A receptor-mediated responses in the hippocampus but not in the DRN. Whether this differential effect is causally related to inverse agonist activity is unclear. The qualitatively different nature of the antagonism in the hippocampus versus the DRN clearly distinguishes the compounds from neutral antagonists, such as N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-2-pyridinylcyclo-hexanecarboxamide (WAY-100635).


Cyclohexanecarboxylic Acids/pharmacology , Hippocampus/drug effects , Piperazines/pharmacology , Raphe Nuclei/drug effects , Serotonin 5-HT1 Receptor Agonists , Serotonin Receptor Agonists/pharmacology , Animals , Guanosine 5'-O-(3-Thiotriphosphate)/metabolism , HeLa Cells , Hippocampus/physiology , Humans , Male , Pyridines/pharmacology , Radioligand Assay , Raphe Nuclei/physiology , Rats , Rats, Wistar , Receptor, Serotonin, 5-HT1A/drug effects , Receptor, Serotonin, 5-HT1A/physiology
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