长效H2受体拮抗剂-拉呋替丁的合成

以2-溴-4-(哌啶基甲基)吡啶为原料,与2-丁烯-1,4-二醇醚化,经氯化、G abrie l反应、肼解,然后再与2-呋喃甲硫基-S-氧代乙酸对硝基苯酚酯进行胺解反应,制得第二代长效H2受体拮抗剂拉呋替丁,总收率为29.89%[以2-溴-4-(哌啶基甲基)吡啶计]。     

High constitutive activity of native H3 receptors regulates histamine neurons in brain

Some G-protein-coupled receptors display 'constitutive activity', that is, spontaneous activity in the absence of agonist. This means that a proportion of the receptor population spontaneously undergoes an allosteric transition, leading to a conformation that can bind G proteins. The process has been shown to occur with recombinant receptors expressed at high density, and/or mutated, but also non-mutated recombinant receptors expressed at physiological concentrations. Transgenic mice that express a constitutively active mutant of the beta2-adrenergic receptor display cardiac anomalies; and spontaneous receptor mutations leading to constitutive activity are at the origin of some human diseases. Nevertheless, this process has not previously been found to occur in animals expressing normal levels of receptor. Here we show that two isoforms of the recombinant rat H3 receptor display high constitutive activity. Using drugs that abrogate this activity ('inverse agonists') and a drug that opposes both agonists and inverse agonists ('neutral antagonist'), we show that constitutive activity of native H3 receptors is present in rodent brain and that it controls histaminergic neuron activity in vivo. Inverse agonists may therefore find therapeutic applications, even in the case of diseases involving non-mutated receptors expressed at normal levels.     

A novel class (H3) of histamine receptors on perivascular nerve terminals

Two types of histamine receptor, the H1- and H2-receptors, are found not only on vascular smooth muscle cells but on the perivascular autonomic nerve terminals. Activation of the prejunctional histamine receptors modifies transmitter release from the nerve terminals. Recently, histamine was shown to inhibit its own release from depolarized slices of rat cerebral cortex. This phenomenon was found to be mediated by a novel class of histamine receptor, the H3-receptor, that was pharmacologically distinct from the H1- and H2-receptors. Up to now, there has been no indication whether this third class of histamine receptor is present in any tissue other than the brain. We report here that histamine depresses sympathetic neurotransmission in the guinea-pig mesenteric artery by interacting with histamine H3-receptors on the perivascular nerve terminals. The pharmacological properties of these receptors are similar to those reported for the H3-receptors in the brain. Our data provide evidence for the existence of H3-receptors in the autonomic nervous system.     

Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors

Many pathological processes, including those causing allergies and autoimmune diseases, are associated with the presence of specialized subsets of T helper cells (TH1 and TH2) at the site of inflammation. The diversity of TH1 and TH2 function is not predetermined but depends on signals that drive the cells towards either subset. Histamine, released from effector cells (mast cells and basophils) during inflammatory reactions can influence immune response. Here we report that histamine enhances TH1-type responses by triggering the histamine receptor type 1 (H1R), whereas both TH1- and TH2-type responses are negatively regulated by H2R through the activation of different biochemical intracellular signals. In mice, deletion of H1R results in suppression of interferon (IFN)-gamma and dominant secretion of TH2 cytokines (interleukin (IL)-4 and IL-13). Mutant mice lacking H2R showed upregulation of both TH1 and TH2 cytokines. Relevant to T-cell cytokine profiles, mice lacking H1R displayed increased specific antibody response with increased immunoglobulin-epsilon (IgE) and IgG1, IgG2b and IgG3 compared with mice lacking H2R. These findings account for an important regulatory mechanism in the control of inflammatory functions through effector-cell-derived histamine.     

Auto-inhibition of brain histamine release mediated by a novel class (H3) of histamine receptor

Although histaminergic neurones have not yet been histochemically visualized, there is little doubt that histamine (HA) has a neurotransmitter role in the invertebrate and mammalian central nervous system. For example, a combination of biochemical, electrophysiological and lesion studies in rats have shown that histamine is synthesized in and released from a discrete set of neurones ascending through the lateral hypothalamic area and widely projecting in the telencephalon. Histamine acts on target cells in mammalian brain via stimulation of two classes of receptor (H1 and H2) previously characterized in peripheral organs and probably uses Ca2+ and cyclic AMP, respectively, as second messengers. It is well established that several neurotransmitters affect neuronal activity in the central nervous system through stimulation not only of postsynaptic receptors, but also of receptors located presynaptically which often display distinct pharmacological specificity and by which they may control their own release. Such 'autoreceptors' have been demonstrated (or postulated) in the case of noradrenaline, dopamine, serotonin, acetylcholine and gamma-aminobutyric acid (GABA) neurones but have never been demonstrated for histamine. We show here that histamine inhibits its own release from depolarized slices of rat cerebral cortex, an action apparently mediated by a class of receptor (H3) pharmacologically distinct from those previously characterized, that is, the H1 and H2 receptors.     

Stimulation of oligodendroglial proliferation and maturation by interleukin-2

There exists considerable evidence that the growth of glial cells can be influenced by T-cell-derived lymphokines and monokines. Astrocytes proliferate in the presence of mitogen- or antigen-stimulated T-cell supernatants, supernatants from human T-lymphotropic virus (HTLV)-transformed T cells, and purified human interleukin-1 (IL-1; ref. 4). Oligodendrocytes proliferate and differentiate when incubated with supernatants from mitogen-activated or HTLV-transformed T cells. In addition, we have recently purified a T-cell-derived lymphokine of relative molecular mass 30,000, termed glial growth promoting factor (GGPF), which specifically stimulates the proliferation of oligodendrocytes. The traditional role of interleukins 1 and 2 is in the initiation, propagation and regulation of the immune response. IL-1, released by a variety of cells including monocytes, stimulates T cells to produce IL-2; IL-2 in turn induces the expansion of T cells that is critical for immune responsiveness. Recently, IL-2 has been shown to induce B-cell proliferation and immunoglobulin secretion, indicating that its action is not restricted to T cells. We now report that recombinant human IL-2 influences the growth of glial cells--specifically, the proliferation and differentiation of oligodendrocytes. IL-2 may have a role in the inflammatory neural lesions of multiple sclerosis patients and in the growth of brain glia during injury or disease.     

Stimulation of the Na/H exchanger of sea urchin eggs by phorbol ester

On fertilization of a sea urchin egg, marked changes occur in the cytoplasmic concentration of calcium and hydrogen ions. These ionic signals represent the necessary and sufficient stimuli for the increased metabolism, protein synthesis and DNA synthesis that constitute egg activation. Cytoplasmic alkalinization, the major immediate cause of the increased rate of protein synthesis which occurs at fertilization, arises because the sperm-induced intracellular calcium transient activates a coupled flux of sodium ions and hydrogen ions across the oolemma. The experiments reported here suggest that the second messenger which links the activation of the Na/H exchange to the calcium transient may be a substance which stimulates protein kinase C8, as 12-O-tetradecanoyl phorbol acetate (TPA), a known activator of protein kinase C9, appears to stimulate protein synthesis by turning on the Na/H exchanger and causing a cytoplasmic alkalinization. Our data indicate that one consequence of treating other tissues with TPA, a tumour promoter, may be an increase in intracellular pH.     

西替利嗪的抗组胺H1受体作用

目的观察西替利嗪的抗组胺H1受体作用.方法采用离体气管环试验分析pA2,以小鼠皮肤通透性试验和组胺致休克试验观察药效.结果西替利嗪10-7～10-6mol·L一1可剂量依赖性地对抗组胺引起的气管环收缩,使组胺的量效曲线平行右移,pA2为7.378 1,西替利嗪0.06～O.mg·kg-1口服给药可显著对抗组胺引起的小鼠皮肤血管通透性的增高,使蓝染面积显著缩小,蓝染皮肤伊文思蓝含量显著降低,当组胺用量为3.2μg时,其Ec50分别为0.177 mg·kg-1和0.379ng·kg-1.西替利嗪0.056～O.50 mg·