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Synthesis and Properties of 2-(4-Substituted)butyl Derivatives of Some 2,3-Dihydro-1,3-dioxo-1H-pyrrolo [3,4-c]pyridines.-All the title compounds (V) show strong analgesic activity, suppress spontaneous locomotor activity and prolonged barbiturate sleep. Moreover, the majority of compounds (V) significantly decreases systolic and diastolic blood pressure. -(SLADOWSKA, H.; SZKATULA, D.; FILIPEK, B.; MACIAG, D.; SAPA, J.; ZYGMUNT, M.; Pharmazie 56 (2001) 2, 133-138; Dep. Chem. Drugs, Wroclaw Univ. Med., PL-50-137 Wroclaw, Pol.; EN)

Pyrazine derivativesPyrazine derivatives R 0550 Investigations on the Synthesis and Pharmacological Properties of 4-Alkoxy-2-[2-hydroxy-3-(4-aryl-1-piperazinyl)propyl]-6-methyl-1H-pyrrolo[3,4-c]pyri-dine-1,3(2H)-diones. -All the title compounds (III) exhibit potent analgesic activity which is superior to that of acetylsalicylic acid in two different tests. Furthermore, most of the imides suppress significantly spontaneous locomotor activity in mice. -(SLADOWSKA*, H.; FILIPEK, B.; SZKATULA, D.; SABINIARZ, A.; KARDASZ, M.; POTOCZEK, J.; SIEKLUCKA-DZIUBA, M.; RAJTAR, G.; KLEINROK, Z.; LIS, T.; Farmaco 57 (2002) 11, 897-908; Dep. Chem. Drugs, Wroclaw Univ. Med., PL-50-137 Wroclaw, Pol.; Eng.) -M. Kowall 10-162

Numerous studies have proven that both stimulation and blockade of 5-HT1A and the blockade of 5-HT7 receptors might cause the anxiolytic-like effects. Biased agonists selectively activate specific signaling pathways. Therefore, they might offer novel treatment strategies. In this study, we investigated the anxiolytic-like activity, as well as the possible mechanism of action of 1-[(2,5-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-17). In our previous experiments, HBK-17 showed high affinity for 5-HT1A and 5-HT7 receptors and antidepressant-like properties. We performed the four plate test and the elevated plus maze test to determine anxiolytic-like activity. Toward a better understanding of the pharmacological properties of HBK-17 we used various functional assays to determine its intrinsic activity at 5-HT1A, 5-HT2A, 5-HT7, and D2 receptors and UHPLC-MS/MS method to evaluate its pharmacokinetic profile. We observed the anxiolytic-like activity of HBK-17 in both behavioral tests and the effect was reversed by the pretreatment with WAY-100635, which proves that 5-HT1A receptor activation was essential for the anxiolytic-like effect. Moreover, the compound moderately antagonized D2, weakly 5-HT7 and very weakly 5-HT2A receptors. We demonstrated that HBK-17 preferentially activated ß-arrestin signaling after binding to the 5-HT1A receptor. HBK-17 was rapidly absorbed after intraperitoneal administration and had a half-life of about 150 min. HBK-17 slightly penetrated the peripheral compartment and showed bioavailability of approximately 45%. The unique pharmacological profile of HBK-17 encourages further experiments to understand its mechanism of action fully.

2005 Medicinal chemistry V 1100Investigations on the Synthesis and Pharmacological Properties of N-Substituted Derivatives of 4-Alkoxy-6-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones. -9 title compounds of type (I) or (II) are prepared and their pharmacological properties are studied. In the "writhing syndrome" test all compounds exhibit a potent analgesic activity which is superior to that of acetylsalicylic acid. In the "hot plate" test imides such as (Ia) and (II) also act stronger than aspirin. -(SLADOWSKA*, H.; FILIPEK, B.; SZKATULA, D.; SAPA, J.; BEDNARSKI, M.; CIOLKOWSKA, M.; Farmaco 60 (2005) 1, 53-59; Dep. Chem. Drugs, Wroclaw Univ. Med., PL-50-137 Wroclaw, Pol.; Eng.) -M. Bohle 23-231

Derivatives of 5,5-Diphenylhydantoin -[such as (VII) and (X)]. -(KIEC-KONONOWICZ*, K.; STADNICKA, K.; MITKA, A.; PEKALA, E.; FILIPEK, B.; SAPA, J.; ZYGMUNT, M.; Eur. J. Med. Chem. 38 (2003) 6, 555-566; Dep. Chem. Technol. Drugs, Coll. Med., Jagiellonian Univ., PL-30-688 Krakow, Pol.; Eng.) -M. Kowall 43-107

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Background Antiplatelet drugs have been used in the treatment of acute coronary syndromes and for the prevention of recurrent events. Unfortunately, many patients remain resistant to the available antiplatelet treatment. Therefore, there is a clinical need to synthesize novel antiplatelet agents, which would be associated with different pathways of platelet aggregation, to develop an alternative or additional treatment for resistant patients. Recent studies have revealed that 5-HT2A receptor antagonists could constitute alternative antiplatelet therapy. Methods Based on the structures of the conventional 5-HT2A receptor ligands, two series of compounds with 4-phenylcyclohexane-5-spiro- or 5-methyl-5-phenyl-hydantoin core linked to various arylpiperazine moieties were synthesized and their affinity for 5-HT2A receptor was assessed. Further, we evaluated their antagonistic potency at 5-HT2A receptors using isolated rat aorta and cells expressing human 5-HT2A receptors. Finally, we studied their anti-aggregation effect and compared it with ketanserin and sarpogrelate, the reference 5-HT2A receptor antagonists. Moreover, the structure–activity relationships were studied following molecular docking to the 5-HT2A receptor model. Results Functional bioassays revealed some of the synthesized compounds to be moderate antagonists of 5-HT2A receptors. Among them, 13, 8-phenyl-3-(3-(4-phenylpiperazin-1-yl)propyl)-1,3-diazaspiro[4.5]decane-2,4-dione, inhibited collagen stimulated aggregation (IC50 = 27.3 μM) being more active than sarpogrelate (IC50 = 66.8 μM) and comparable with ketanserin (IC50 = 32.1 μM). Moreover, compounds 2–5, 9–11, 13, 14 inhibited 5-HT amplified, ADP- or collagen-induced aggregation. Conclusions Our study confirmed that the 5-HT2A antagonists effectively suppress platelet aggregation and remain an interesting option for the development of novel antiplatelet agents with an alternative mechanism of action.