The future of 5-HT1A receptor agonists. (arylpiperazine derivatives)

Mitsukuni Murasaki and Sadanori Miura: The Future of 5-HT_1A Receptor Agonists. (Aryl-Piperazine Derivatives) Prog. Neuro- Psychopharmacol-& Biol Psychiat, 1992, 16(6): 833–845.

1. 1. At present the dominant position among anti-anxiety medications has changed from meprobamate to the benzodiazepine derivatives.

2. 2. In order to avoid benzodiazepine's (BZ) undesirable side effects such as impairment of psycho-motor function, memory impairment, low dose dependence and withdrawal symptoms, a third generation anxiolytic agent, buspirone, the focus of the aryl-piperazine group of anti-anxiety agents, has been introduced recently.

3. 3. Aryl-piperazine derivatives work as 5-HT_1A receptor partial agonists and are known as serotonin normalizers.

4. 4. Therefore, they are expected to have not only an anxiolytic function but also an anti-depressant effect as well.

5. 5. A characteristic of the aryl-piperazine derivatives is that they have no sedative and muscle relaxant effects, and they do not have BZ's undesirable side-effects, especially in regard to withdrawal symptoms. However they have a rather weak anxiolytic action and a slow onset of action.

6. 6. Aryl-piperazine derivatives will not take the place of BZ, but the use of BZ and buspirone as bridge medications, making the most of the strong points of both, can be proposed as a way to compensate for their respective disadvantages.

Detection of the homology among proteins by immunochemical cross-reactivity between denatured antigens. Application to the glyceraldehyde 3-phosphate dehydrogenases from different species

It was previously proposed that an immunological cross-reaction between two denatured proteins is evidence for an homology betweeen their amino sequence (Arnon &; Maron, 1971; Arnheim et al., 1971) and that detection of such a cross-reaction could then be a rapid method to detect sequence homologies (Zakin et al., 1978). In order to test the possibilities of such a methodology, using proteins of known structure, glyceraldehyde 3-phosphate dehydrogenases from different sources are compared by immunochemical techniques. The antibodies raised against the native enzyme from E. coli K 12 can only recognize the homologous antigen, the glyceraldehyde 3-phosphate dehydrogenase from B. stearothermophilus and to a lesser extent that from halibut. In contrast, the antibodies raised against the denatured enzyme from E. coli K 12 can recognize the glyceraldehyde 3-phosphate dehydrogenases from man, ostrich, chicken, sturgeon, halibut, lobster and yeast, when in their denatured state. The present results show unambiguously that through exposure of buried sequences, the immunochemical detection of sequence homologies among proteins is more discriminating when unfolded proteins are used, rather than native ones. It is also proposed that the use of denatured proteins both as immunogens and antigens would be a useful tool in studying biochemical evolution.     

The involvement of glutamatergic transmission in the mechanism of movement disorders induced by reversive rotation of white mice

The ability of the selective non-competitive NMDA receptor blocker MK-801 and a series of new glutamate antagonists—the adamantane derivatives IEM-1754 and IEM-1857 and phencyclidine (IEM-1925)—to prevent movement disorders induced by reversive rotation in mice was studied. I.p. MK-801 at a dose of 0.15 ml and IEM-1754 at a dose of 5.0 mg/kg prevented the development of akinesia in response to reversive rotation, as effectively as scopolamine, a known agent which provides effective prophylaxis for movement diseases. IEM-1857, the quaternary analog of IEM-1754, was not effective. IEM-1925 significantly increased the responses of mice to reversive rotation, possibly because of its high activity in relation to other subtypes of glutamate receptors. These data provide evidence for the involvement of glutamatergic transmission in the mechanism of movement disorders of vestibular origin. Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 85, No. 4, pp. 497–501, May, 1999.     

Time of onset of action of acrivastine in the skin of pollen-allergic subjects

The purpose of this study was to assess the time of onset of action of acrivastine in suppressing the wheal response to histamine (10 mg/ml) and allergen (10000 and 100000 BU/ml) in the skin prick test. Ten subjects with a well-documented allergy to pollen received single doses of 8 mg of acrivastine and placebo according to a randomized, double-blind, placebo-controlled, crossover treatment design. Duplicate skin prick tests were performed 0, 15, 20, 25, 30, and 60 min after medication. The results demonstrated a statistically significant suppression of the wheal reactions 15–20 min after medication, depending on the reaction producers used. The sum of all three producers showed a statistically significant effect on the wheal reaction 15 min after medication. The upper 95% confidence limit for time lag from dosing of acrivastine until reduction from placebo level commences was 6.5 min. The study substantiates that orally administered acrivastine has a rapid onset of action in the skin of allergic subjects. The results indicate that allergen SPT is a more sensitive tool for studying antihistaminergic activity than histamine SPT.     

Generalization tests with intraventricularly applied pro-enkephalin B-derived peptides in rats trained to discriminate the opioid kappa receptor agonist ethylketocyclazocine

Rats were trained in a two-lever food-reinforced procedure to discriminate between the effects of saline and the opioid kappa receptor agonist ethylketocyclazocine. After acquisition of this discrimination, generalization tests with opioid peptides such as -endorphin, -neoendorphin, dynorphin A and some dynorphin-derived peptides were conducted. The rats dose-dependently generalized the effects of intracerebroventricularly injected ethylketocyclazocine but not -endorphin, -neoendorphin, dynorphin A_1–8, dynorphin A_1–13, D-Cys²-L-Cys⁵-dynorphin A_1–13 or dynorphin A. D-Cys²-L-Cys⁵-dynorphin A_1–13, in contrast to dynorphin A itself, dose-dependently caused analgesia and catatonia that was reversible with naloxone. Studies into the receptor preference of this derivative, using the technique of selective tolerance, revealed that this dynorphin derivative is almost devoid of kappa-receptor activity.     

Unexpected potentiation by discriminant benzamide derivatives of stereotyped behaviours elicited by dopamine agonists in mice

Summary Among four stereotyped manifestations that can be simultaneously quantified in mice treated with apomorphine (APO), two of them (climbing and sniffing) emerge at low APO dosages (below 1 mg/kg) whereas licking and sniffing require APO dosages above 6 mg/kg. However, in mice pretreated (either i.p. or i.c.v.) with sulpiride (especially the levo isomer) or (±)amisulpride in moderate dosage stereotyped licking and sniffing are elicited by APO in much lower dosage (0.75 mg/kg). As a consequence, in mice pretreated with these benzamide derivatives and receiving 0.75 mg/kg APO, a biphasic effect was observed: licking and gnawing progressively appear at low dosages, whereas they are progressively abolished at higher dosages.This potentiation of the effects of APO by (±)amisulpride is even more obvious (maximal scores increased) with larger test-doses of the dopamine agonist (up to 5 mg/kg). Amisulpride also allows the emergence of the two stereotyped behaviours in mice receiving other dopamine agonists in subthreshold dosages (Dipropyl 5,6-ADTN, dexamphetamine or cocaine). The potentation of APO is still observed after dopamine depletion by reserpine and -methylparatyrosine, whereas that of dexamphetamine is abolished. In contrast with the benzamide derivatives, haloperidol does not potentiate at any dosage the effect of APO but, at 0.15 mg/kg, suppresses licking and gnawing elicited by 0.75 mg/kg APO in mice pretreated with 6.25 mg/kg amisulpride or veralipride.Among a series of dopamine antagonists belonging to various chemical classes, only a number of discriminant benzamide derivatives (DBD), previously shown to differentially antagonise several APO-induced behavioural manifestations in rats (sulpiride, amisulpride, tiapride, sultopride, DO 701, LUR 2366 but not metoclopramide) potentiate APO (0.75 mg/kg) regarding licking and gnawing. In contrast, potentiation is not observed, even for a higher test dose of APO, with haloperidol, thioproperazine, pimozide, mezilamine, thioridazine or metoclopramide at any dosage tested.For the various DBD, the two stereotyped behaviours emerge at dosages at which climbing starts to be inhibited, suggesting that selective blockade of some inhibitory response to APO is responsible for the potentiation. Among other hypothesis the possibility that the peculiar behavioural properties of DBD is related to their differential recognition of two classes of dopaminergic binding sites is discussed.     

槲皮素的结构修饰及生物活性研究进展

槲皮素是蔬菜、水果、中药中常见的黄酮类化合物,是天然的抗氧化剂,具有抗癌、抗糖尿病、抗菌、抗炎、抗病毒等生物活性。由于槲皮素生物利用度低,限制了其在临床上的应用。通过各种方法设计和合成新的槲皮素衍生物,以改善其缺点,进而发挥预防和治疗疾病的作用。通过对槲皮素衍生物的合成及其抗癌、抗糖尿病、抗炎、抗菌和抗病毒活性进行综述,并对其构效关系进行分析,为天然化合物的开发和利用奠定基础。     

A Novel Composite Skin Graft Technique with Fat Derivatives

Skin grafting, although a relatively classic and well-known technique, still has multiple disadvantages such as secondary contracture of the skin graft, sunken depression, poor elasticity, and color mismatch. Adding adipose tissues significantly improved the graft appearance compared to traditional skin grafting methods. Herein, we report two cases of modified skin graft procedures, both showing positive outcomes. In case 1, a mechanically processed fat-derived product was injected into the lower half of the skin graft area. In case 2, left upper eyelid blepharoplasty was performed, and the orbital fat strip was transferred and placed under the recipient area on the right side. Hair growth was observed only in case 1, whereas the extent of sunken depression was significantly reduced in both cases. Compared to traditional skin grafting methods, adding fat components to the skin graft recipient area improved the appearance and blood supply, together with enhancing the regenerative rate.     

Ectodermal dysplasias: not only 'skin' deep

The ectodermal dysplasias (EDs) are a large and complex nosologic group of diseases; more than 170 different pathologic clinical conditions have been identified. Despite the great number of EDs described so far, few causative genes have been identified. We review EDs in the light of the most recent molecular findings and propose a new classification of EDs integrating both molecular-genetic data and corresponding clinical findings of related diseases.     

PE重组免疫毒素在肿瘤导向治疗中的应用

绿脓杆菌外毒素A(PE)经过修饰后失去了与细胞结合的能力,将单克隆抗体的Fv段或细胞因子作为导向分子与修饰后的PE通过DNA重组技术融合,获得重组的免疫毒素,这种免疫毒素通过导向分子将毒素带到靶细胞,并杀伤靶细胞,因而被广泛运用于肿瘤的导向治疗。