Synthesis and structure-activity relationship of 1H-indole-3-carboxylic acid pyridine-3-ylamides: a novel series of 5-HT2C receptor antagonists.

A novel series of 1H-indole-3-carboxylic acid pyridine-3-ylamides were synthesized and identified to show high affinity and selectivity for 5-HT(2C) receptor. Among them, 1H-indole-3-carboxylic acid[6-(2-chloro-pyridin-3-yloxy)-pyridin-3-yl]-amide (15k) exhibits the highest affinity (IC(50)=0.5 nM) with an excellent selectivity (>2000 times) over other serotonin (5-HT(1A), 5-HT(2A), and 5-HT(6)) and dopamine (D(2)-D(4)) receptors.

Reactivation of DFP- and paraoxon-inhibited acetylcholinesterases by pyridinium oximes.

Exposure to the organophosphorus nerve agents such as sarin, soman, cyclosarin, and VX causes acute intoxication by inhibiting acetylcholinesterase (AChE), where the serine residue of the active site can attack the phosphorous atom of the organophosphorus agents to form a strong P-O bond. The purpose of the present study was to evaluate new oxime antidotes to reactivate the inhibited AChE. We have designed and synthesized several new oximes, and have evaluated the substances that differ from the currently used oximes in linker between the two pyridinium rings. The potency of newly synthesized oximes was compared with two currently used AChE reactivators (2-PAM, HI-6). The reactivation potencies of the bis-pyridinium oximes connected with a (CH(2))(n) linker between the two quaternary nitrogen atoms were evaluated with housefly (HF) AChE inhibited by diisopropyl fluorophosphates (DFP) and by paraoxon. The bis-pyridinium oximes showed stronger activity compared with mono-pyridinium oxime, and the magnitude of reactivation potency depended on the length of the methylene linker. The potency order was (CH(2))<(CH(2))(2)<(CH(2))(3)>(CH(2))(4)>(CH(2))(7). A (CH(2))(3) linker was optimal in HF AChE inhibited by either DFP or paraoxon. Thus, bis-pyridinium oxime 5 which has (CH(2))(3) linker showed the highest activity in this series of compounds. Interestingly, 5 was not as active as 2-PAM, showing that the position of the oxime group on the pyridinium ring is also very important for the reactivation potency.

Synthesis and antioxidant activities of 3,5-dialkoxy-4-hydroxycinnamamides.

A series of 3,5-dialkoxy-4-hydroxycinnamamides 6 and 7 was synthesized, and their antioxidant activity was assessed using the thiobarbituric acid reactive substance (TBARS) assay. Interestingly, cinnamamides with longer alkoxy groups on the C-3 and C-5 positions display enhanced inhibition, and most of the compounds in the series tested exhibit excellent lipid peroxidation inhibitory activities. Some cinamamides bearing hexyloxy or 2,6-di-tert-butyl-4-methyl phenol groups have submicromolar inhibitory activities.

Discovery of 3-aryl-3-methyl-1H-quinoline-2,4-diones as a new class of selective 5-HT6 receptor antagonists.

A 5,7-dichloro-3-phenyl-3-methyl-quinoline-2,4-dione (11a) has been identified in a random screen as a lead for 5-HT(6) antagonist. During the lead optimization process, several analogs were synthesized and their biological activities were investigated. Within this series, several compounds display high binding affinity and selectivity for the 5-HT(6) receptor. In particular, 3-(4-hydroxyphenyl)-3-methyl-quinoline-2,4-dione (12f) exhibits high affinity (K(i)=12.3 nM) for 5-HT(6) receptor with good selectivity over other serotonin and dopamine (D(1)-D(4)) receptor subtypes. In a functional adenylyl cyclase stimulation assay, this compound exhibited considerable antagonistic activity (IC(50)=0.61 microM).

Synthesis and evaluation of 4-hydroxyphenylacetic acid amides and 4-hydroxycinnamamides as antioxidants.

4-Hydroxyphenylacetic acid amides and 4-hydroxycinnamamides were synthesized and their antioxidant and neuroprotective activities were evaluated. Among the prepared compounds, 8b, and exhibited potent inhibition of lipid peroxidation in rat brain homogenates, and marked DPPH radical scavenging activities. Furthermore, and exhibited neuroprotective action against the oxidative damage induced by the exposure of primary cultured rat cortical cells to H(2)O(2), xanthine/xanthine oxidase, or Fe(2+)/ascorbic acid. Based on these results, we found that was the most potent antioxidant among the compounds tested.

The crystal structure of KR-21042, an analgesic capsaicinoid.

The crystal structure of KR-21042, N-(3-Phenylpropyl)-4-hydroxy-3-methoxyphenylacetamide, was determined by single crystal X-ray diffraction analysis. The compound was recrystallized from a mixture of ethylacetate and n-hexane in monoclinic, space group P21/c, with a = 16.622(1), b = 6.215(1), c = 15.802(1) A, P= 104.97(1), and Z = 4. The calculated density is 1.261 g/cm3. The structure was solved by the direct method and refined by full matrix least-squares procedure to the final R value of 0.068 for 2332 observed reflections.