Adam Bucki

Novel arylsulfonamide derivatives with 5‑HT6/5-HT7 receptor antagonism targeting behavioral and psychological symptoms of dementia

In order to target behavioral and psychological symptoms of dementia (BPSD), we used molecular modeling-assisted design to obtain novel multifunctional arylsulfonamide derivatives that potently antagonize 5-HT(6/7/2A) and D2 receptors, without interacting with M1 receptors and hERG channels. In vitro studies confirmed their antagonism of 5-HT(7/2A) and D2 receptors and weak interactions with key antitargets (M1R and hERG) associated with side effects. Marked 5-HT6 receptor affinities were also observed, notably for 6-fluoro-3-(piperidin-4-yl)-1,2-benzoxazole derivatives connected by a 3-4 unit alkyl linker with mono- or bicyclic, lipophilic arylsulfonamide moieties. N-[4-[4-(6-Fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]butyl]benzothiophene-2-sulfonamide (72) was characterized in vitro on 14 targets and antitargets. It displayed dual blockade of 5-HT6 and D2 receptors and negligible interactions at hERG and M1 receptors. Unlike reference antipsychotics, 72 displayed marked antipsychotic and antidepressant activity in rats after oral administration, in the absence of cognitive or motor impairment. This profile is particularly attractive when targeting a fragile, elderly BPSD patient population.

Antidepressant- and anxiolytic-like activity of 7-phenylpiperazinylalkyl-1,3-dimethyl-purine-2,6-dione derivatives with diversified 5-HT1A receptor functional profile

Continuing our earlier study in a group of purine-2,6-dione derivatives of long chain arylpiperazines (LCAPs), a series of 8-unsubstituted 7-phenylpiperazin-4-yl-alkyl (4-14) and 7-tetrahydroisoquinolinyl-alkyl (15-17) analogues were synthesized and their serotonin 5-HT1A, 5-HT2A, 5-HT6, 5-HT7 and dopamine D2 receptor affinities were determined. The study allowed us to identify some potent 5-HT1A receptor ligands with additional moderate affinity for 5-HT2A, 5-HT7 and dopamine D2 receptors. Compounds 9, 12, 13 and 14, with the highest 5HT1A receptor affinity, were selected for further functional in vivo studies and behavioural evaluation of antidepressant- and antianxiety-like activity. Compounds 9, 12 and 13 showed features of agonists of pre- and/or post-synaptic 5-HT1A receptors, whereas 14 was classified as an antagonist of postsynaptic sites. Moreover, derivatives 9 and 14 acted as antagonists of 5-HT2A receptors. In behavioural studies, compounds 9 and 13 showed antidepressant-like activity in the mouse forced swim test, and their effects were similar or stronger than those of imipramine. Compounds 9, 12 and 14 displayed potential anxiolytic-like properties in the mouse four-plate test, similar or even greater than those of the reference anxiolytic drug, diazepam.

Novel Mannich Bases, 5‐Arylimidazolidine‐2,4‐dione Derivatives with Dual 5‐HT1A Receptor and Serotonin Transporter Affinity

A computer aided ligand design study of imidazolidine‐2,4‐dione derivatives was conducted in order to obtain compounds with dual 5‐HT1A receptor and serotonin transporter (SERT) affinity. According to molecular modeling results, series of Mannich bases were chosen and synthesized. Investigated compounds were tested for 5‐HT1A, 5‐HT2A, α1 and SERT affinity. Two selected compounds (5, 9) were characterized in functional experiments and possessed a pharmacological profile which may enhance SERT blocking efficacy – 5‐HT1A partial agonism and 5‐HT2A antagonism in one molecule. Furthermore these compounds displayed satisfactory selectivity over adrenergic α1 receptors. The most promising compounds, 5‐arylimidazolidine‐2,4‐dione derivatives with 4‐(3‐chlorophenyl)piperazinylmethyl moiety were tested for antidepressant and anxiolytic activity. In particular, compound 5 (5‐(2‐methoxyphenyl)‐3‐{1‐[4‐(3‐chlorophenyl)piperazin‐1‐yl]methyl}‐imidazolidine‐2,4‐dione), tested in the forced swim test in mice, exhibited a favorable antidepressant‐like profile without affecting spontaneous locomotor activity.

Metabolic carbonyl reduction of anthracyclines — role in cardiotoxicity and cancer resistance. Reducing enzymes as putative targets for novel cardioprotective and chemosensitizing agents

SummaryAnthracycline antibiotics (ANT), such as doxorubicin or daunorubicin, are a class of anticancer drugs that are widely used in oncology. Although highly effective in cancer therapy, their usefulness is greatly limited by their cardiotoxicity. Possible mechanisms of ANT cardiotoxicity include their conversion to secondary alcohol metabolites (i.e. doxorubicinol, daunorubicinol) catalyzed by carbonyl reductases (CBR) and aldo-keto reductases (AKR). These metabolites are suspected to be more cardiotoxic than their parent compounds. Moreover, overexpression of ANT-reducing enzymes (CBR and AKR) are found in many ANT-resistant cancers. The secondary metabolites show decreased cytotoxic properties and are more susceptible to ABC-mediated efflux than their parent compounds; thus, metabolite formation is considered one of the mechanisms of cancer resistance. Inhibitors of CBR and AKR were found to reduce the cardiotoxicity of ANT and the resistance of cancer cells, and therefore are being investigated as prospective cardioprotective and chemosensitizing drug candidates. In this review, the significance of a two-electron reduction of ANT, including daunorubicin, epirubicin, idarubicin, valrubicin, amrubicin, aclarubicin, and especially doxorubicin, is described with respect to toxicity and efficacy of therapy. Additionally, CBR and AKR inhibitors, including monoHER, curcumin, (−)-epigallocatechin gallate, resveratrol, berberine or pixantrone, and their modulating effect on the activity of ANT is characterized and discussed as potential mechanism of action for novel therapeutics in cancer treatment.

Arylpiperazinylalkyl derivatives of 8-amino-1,3-dimethylpurine-2,6-dione as novel multitarget 5-HT/D receptor agents with potential antipsychotic activity.

Abstract A series of new 7-arylpiperazinylalkyl-1,3-dimethyl-purine-2,6-dione derivatives with diversified 8-amino substituent in 8 position was synthesized and their 5-HT1A, 5-HT2A, 5-HT6, 5-HT7, and D2 receptor affinities were determined. The binding study allowed identifying some potent 5-HT1A/5-HT2A/5-HT7/D2 ligands. The most interesting because of their multireceptor profile were 8-piperidine (30–35) and 8-dipropylamine (45–47) analogs with four and five carbon aliphatic linkers. The selected compounds 24, 31, 34, 39, 41, 43, 45, and 46 in the functional in vitro evaluation for all targeted receptors showed significant partial D2 agonist, partial 5-HT1A agonist, and 5-HT2A antagonist properties. The advantageous in vitro affinity of compound 34 for 5-HT1A and D2 receptors has been explained by means of molecular modeling, taking into consideration its partial agonist activity towards the latter one. In behavioral studies, compounds 32 and 34 revealed antipsychotic-like properties, significantly decreasing d-amphetamine-induced hyperactivity in mice.

Synthesis and biological evaluation of 2-fluoro and 3-trifluoromethyl-phenyl-piperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione as potential antidepressant agents

Abstract A series of 2-fluoro and 3-trifluoromethylphenylpiperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (4–21) were synthesized and evaluated for their serotonin (5-HT1A/5-HT7) receptor affinity and phosphodiesterase (PDE4B and PDE10A) inhibitor activity. The study enabled the identification of potent 5-HT1A, 5-HT7 and mixed 5-HT1A/5-HT7 receptor ligands with weak inhibitory potencies for PDE4B and PDE10A. The tests have been completed with the determination of lipophilicity and metabolic stability using micellar electrokinetic chromatography (MEKC) system and human liver microsomes (HLM) model. In preliminary pharmacological in vivo studies, selected compound 8-(5-(4-(2-fluorophenyl)piperazin-1-yl)pentyl)-1,3,7-trimethyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (9) behaved as a potential antidepressant in forced swim test (FST) in mice. Moreover, potency of antianxiety effects evoked by 9 (2.5 mg/kg) is greater than that of the reference anxiolytic drug, diazepam. Molecular modeling revealed that fluorinated arylpiperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione have major significance for the provision of lead compounds for antidepressant and/or anxiolytic application.

New Arylpiperazinylalkyl Derivatives of 8‐Alkoxy‐purine‐2,6‐dione and Dihydro[1,3]oxazolo[2,3‐f]purinedione Targeting the Serotonin 5‐HT1A/5‐HT2A/5‐HT7 and Dopamine D2 Receptors

To obtain potential antidepressants and/or antipsychotics, a series of new long‐chain arylpiperazine derivatives of 8‐alkoxy‐purine‐2,6‐dione (10–24) and dihydro[1,3]oxazolo[2,3‐f]purinedione (30–34) were synthesized and their serotonin (5‐HT1A, 5‐HT2A, 5‐HT6, 5‐HT7) and dopamine (D2) receptor affinities were determined. The study allowed the identification of some potent 5‐HT1A/5‐HT7/D2 ligands with moderate affinity for 5‐HT2A sites. The binding mode of representative compounds from both chemical classes (11 and 31) in the site of 5‐HT1A receptor was analyzed in computational studies. In functional in vitro studies, the selected compounds 15 and 16 showed antagonistic properties for the evaluated receptors. 8‐Methoxy‐7‐{4‐[4‐(2‐methoxyphenyl)‐piperazin‐1‐yl]‐butyl}‐1,3‐dimethyl‐purine‐2,6‐dione (15) showed a lack of activity in terms and under the conditions of the forced swim, four plate and amphetamine‐induced hyperactivity tests in mice, probably as a result of its high first pass effect in the liver.

The study of the lipophilicity of α-(4-phenylpiperazin-1-yl)-γ-phthalimidobutyramides using chromatographic and computational methods

The lipophilicity of the series of alpha-(4-phenylpiperazin-1-yl)-gamma-phthalimido-butyramides (1-8) has been investigated. Several methods, like reversed-phase thin-layer chromatography and high-performance liquid chromatography using reversed-phase RP18 and IAM.DD2 columns, were applied to determine RMO, log k0 and log k(0IAM) factors. The RP-TLC investigations were performed in mixtures of acetone-water and acetonitrile-water. For RP-HPLC method mixtures of acetonitrile, water and 0.01% TFA were used as the mobile phases while for IAM.DD2 investigations mixtures of acetonitrile and water were applied. The partition coefficients of compounds (1-8) were also calculated with the Pallas and CAChe programs. All the obtained data, both from experimental methods and computational calculations, were compared and a suitable conclusion was reached.

Aminoalkyl Derivatives of 8-Alkoxypurine-2,6-diones: Multifunctional 5-HT1A/5-HT7 Receptor Ligands and PDE Inhibitors with Antidepressant Activity

In the search for potential psychotropic agents, a new series of 3,7‐dimethyl‐ and 1,3‐dimethyl‐8‐alkoxypurine‐2,6‐dione derivatives of arylpiperazines, perhydroisoquinolines, or tetrahydroisoquinolines with flexible alkylene spacers (5–16 and 21–32) were synthesized and evaluated for 5‐HT1A/5‐HT7 receptor affinities as well as PDE4B1 and PDE10A inhibitory properties. The 1‐(4‐(4‐(2‐hydroxyphenyl)piperazin‐1‐yl)butyl)‐3,7‐dimethyl‐8‐propoxypurine‐2,6‐dione (16) and 7‐(2‐hydroxyphenyl)piperazinylalkyl‐1,3‐dimethyl‐8‐ethoxypurine‐2,6‐diones (31 and 32) as potent dual 5‐HT1A/5‐HT7 receptor ligands with antagonistic activity produced an antidepressant‐like effect in the forced swim test in mice. This effect was similar to that produced by citalopram. All the tested compounds were stronger phosphodiesterase isoenzyme inhibitors than theophylline and theobromine. The most potent compounds, 15 and 16, were characterized by 51 and 52% inhibition, respectively, of PDE4B1 activity at a concentration of 10−5 M. Concerning the above findings, it may be assumed that the inhibition of PDE4B1 may impact on the signal strength and specificity resulting from antagonism toward the 5‐HT1 and 5‐HT7 receptors, especially in the case of compounds 15 and 16. This dual receptor and enzyme binding mode was analyzed and explained via molecular modeling studies.

Synthesis and biological evaluation of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential antiplatelet agents

Abstract Despite the substantial clinical success of aspirin and clopidogrel in secondary prevention of ischemic stroke, up to 40% of patients remain resistant to the available antiplatelet treatment. Therefore, there is an urgent clinical need to develop novel antiplatelet agents with a novel mechanism of action. Recent studies revealed that potent alpha 2B-adrenergic receptor (alpha 2B-ARs) antagonists could constitute alternative antiplatelet therapy. We have synthesized a series of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential alpha 2B receptor antagonists. The most potent compound 3, effectively inhibited the platelet-aggregation induced both by collagen and ADP/adrenaline with IC50 of 26.9 μM and 20.5 μM respectively. Our study confirmed that the alpha 2B-AR antagonists remain an interesting target for the development of novel antiplatelet agents with an alternative mechanism of action. Graphical Abstract