Yodchai Boonprakob

In vivo evaluation of substituted 3-amino-1,4-benzodiazepines as anti-depressant, anxiolytic and anti-nociceptive agents.

Oxazepam (CAS 604-75-1) 4a served as building block in the synthesis of substituted 3-amino-1,4-benzodiazepines, which were subsequently tested in various CNS animal models. The hydroxy group of oxazepam was either activated as a chloride (Method A) or as a phosphor-oxy derivative (Method B) giving the desired 3-amino-1,4-benzodiapines 6a-6r in high yields with primary and secondary amines in a typical nucleophilic substitution reaction. Eighteen 3-substituted 1,4-benzodiazepines were prepared and served as new chemical entities and for lead structure discovery. The mixed cholecystokinin (CCK) antagonist 6e showed anxiolytic and antidepressant effects from 10 microg/kg in mice in the elevated x-maze test and the forced swimming test. The CCK1 antagonist 6 g has shown antidepressant effects from the same dose, but lacked anxiolytic properties. Both compounds potentiated at a dose of 0.5 mg/kg morphine antinociception with a maximum possible effect (MPE) about 35%. By assessing initially the MPE of antinocipection for the 18 newly synthesised benzodiazepines in the tail-flick test, 4 other benzodiazepines were found active. In further in vive evaluation the cyclohexyl derivative 6 i displayed anxiolytic, antidepressant and antinociceptive properties as single agent at a dose of 5 mg/kg without toxicity. The benzodiazepines 6i and 6p, which initially showed a higher MPE in terms of morphine potentiation (43/44%) showed analgesic effects as single agents, without having anxiolytic or antidepressant properties. The amino-piperidinyl derivative 6p displayed a similar dose-response relationship to morphine, but was 3 times more potent.

Antidepressant/Anxiolytic and Anti-Nociceptive Effects of Novel 2-Substituted 1,4-Benzodiazepine-2-ones

Oxazepam (4a) has been used as overall starting material in the synthesis of novel 2-substituted 1,4-benzodiazepines. By reacting Oxazepam 4a with commercially available hydrazines, hydrazides, semicarbazide, aminoguanidine and N,N-dimethylamino aniline in ethanol under acetic conditions, a series of diazenyl-1,4-benzodiazepines 5a–5i and 2-amino-1,4-benzodiazepine 5k were obtained in good yields. These novel compounds served as new chemical entities (NCE) for testing in mice. The diazo-benzodiazepine 5d has shown a promising antidepressant effect in initial experiments in vivo at a dose of 5 mg/kg. The highly coloured 2-aminobenzodiazepine derivative 5k showed over a dose range from 5–50 mg/kg an analgesic effect in mice.

Synthesis and evaluation of N-(3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-1H-indole-carboxamides as cholecystokinin antagonists

The structure‐activity relationship optimization of the pyrazoline template 3a resulted in novel 3‐oxo‐1,2‐diphenyl‐2,3‐dihydro‐1H‐pyrazol‐4‐yl)‐indole carboxamides 4a–4e. These non‐peptidal CCK ligands have been shown to act as potent CCK1 ligands in a [125]I‐CCK‐8 receptor binding assay. The best amides (4c and 4d) of this series displayed an IC50 of 20/25 nm for the CCK1 receptor. In a subsequent in‐vivo evaluation using various behaviour pharmacological assays, an anxiolytic effect of these novel 3‐oxo‐1,2‐diphenyl‐2,3‐dihydro‐1H‐pyrazol‐4‐yl)‐indole carboxamides was found at high doses in the elevated plus‐maze. In the despair swimming test, a model for testing antidepressants, an ED50 of 0.33/0.41 mg kg−1 was determined for amide 4c/4d and the antidepressant effect had a magnitude comparable to desimipramine.

The short-term effect of gloving in combination with Traditional Thai Massage, heat, and stretching exercise to improve hand mobility in scleroderma patients

Background: Systemic sclerosis (SSc) is a chronic, multisystem connective tissue disorder characterized by autoimmune activation, microvascular endothelium damage, and excessive collagen proliferation. The most affected hand presents claw hand deformity and microvascular disease. Deformed hands can cause functional disability and decrease the quality of life. A daily home program can improve mobility of scleroderma patients. Objective: We sought to determine the effect of a daily home exercise program on hand mobility among scleroderma patients. Materials and Methods: This was a randomized control trial. Twenty-eight participants were divided into two groups, both of which received the same daily home treatment: Group 1 with gloves (n = 14) and Group 2 without gloves (n = 14). The 2-week daily home program combined traditional Thai massage (TTM) with stretching exercises and heat. Hand mobility was assessed using hand mobility in scleroderma (HAMIS). The study was conducted in patients who were already on vasodilator drugs. Results: Both groups showed a significant improvement in hand mobility after 2 weeks of daily home exercise program (P < 0.05). Wearing the glove, however, resulted in better thumb mobility. Conclusions: A daily home exercise program improved hand mobility among patients with scleroderma and wearing gloves may improve thumb mobility.

Analgesic effects of 5-alkyloxy-4-amino-2(5H)-furanones as cholecystokinin-2 antagonists

4‐Amino‐2(5H)‐furanones were synthesized in high yields over two synthetic steps from readily available mucochloric acid. These 5‐alkyloxy‐4‐amino‐2(5H)‐furanones were screened in a [125]I‐CCK‐8 radioligand receptor binding assay for CCK2 affinity and novel active ligands in the nanomolar range were identified. SAR was optimized leading to the cyclohexyl derivative 25 with an IC50 of 27 nM. Furanone 18 was obtained as a stable crystalline material with an IC50 of 85 nM, but had a higher CCK2 selectivity. It was subsequently tested in the isolated guinea pig ileum assay with sulfated CCK8, and the CCK antagonizing properties of the ligand were confirmed. The CCK2 selective antagonist 18 was found to potentiate analgesia in the tail flick assay in mice, for the strong opiate morphine, the partial opiate agonist tramadol and the tricyclic antidepressant desimipramine.