Complicated intermolecular interactions formed between organofluorine and drug target / 药学学报

Fluorinated compounds, which now make up 20%-25% of all marketed chemical drugs, are playing significant role and showing great potential in medicinal chemistry. Fluorine substitution is always utilized to change the physicochemical properties of the compounds to improve the ADME/T properties. In addition, fluorine substitution leads to improvement of the ligand binding affinity. With respect to molecular level, organofluorine can form various intermolecular interactions with the target proteins, e.g., hydrogen bond, halogen bond, C-F…π interaction, polar interaction and so on. These interactions display unique properties or nature due to the specificity of fluorine atom, which are at the center of attention. This paper reviews the related research background, followed by the research progress of hydrogen bond, halogen bond, C-F…π interaction, polar interaction and some other interactions involved organofluorine.

Research progress in VEGFR-2 inhibitors / 药学学报

Vascular endothelial growth factor receptor (VEGFR-2), a member of the super family of protein tyrosine kinase receptors, plays a vital role in the regulation of tumor metastasis and angiogenesis. Several VEGFR-2 inhibitors have been marketed as antitumor drugs and a range of inhibitors are undergoing clinical or preclinical studies. According to the principle of multi-targeted pharmacolgy, in the field of tumor treatment, nonselective drugs targeting on more than one kinase to inhibit different cell pathways can be more effective than drugs specific for one kinase. Multi-target treatment does not mean abandonment of selectivity, but a precise selectivity for several kinases related to tumor, which is also a big challenge in the development of small molecular antitumor drugs. This paper reviews briefly the advances in research of the VEGFR-2 inhibitors and selectivity strategy in recent years.

Effects of protein tyrosine kinase within the brainstem nucleus tractus solitarius on the ventilatory responses of peripheral chemoreflex / 生理学报

The aim of the present study was to observe whether protein tyrosine kinase (PTK) within the nucleus tractus solitarius (NTS) was involved in the regulation of ventilatory responses of peripheral chemoreflex. The experiments were performed on anesthetized, immobilized and artificially ventilated rabbits. Peripheral chemoreflex was elicited by ventilating the animal with 10% O2-balance 90% N2. Changes in the peak amplitude and frequency of integrated phrenic nerve activity were observed. The ventilatory responses of peripheral chemoreflex following 0.1 microl microinjection within the NTS of either PTK inhibitor genistein (10 mol/L), AMPA glutamate receptor inhibitor CNQX (10 mol/L),or inactive PTK inhibitor daidzein (10 mol/L) were recorded. The results are as follows: Both genistein and CNQX attenuated the ventilatory responses of peripheral chemoreflex, while no changes occurred following daidzein. The amplitude of integrated phrenic nerve discharge and the phrenic burst frequency were decreased by (-21.77+/-6.93)% and (-24.70+/-7.61)% respectively after administration of genistein. CNQX resulted in similar decreases in the amplitude of phrenic nerve discharge (-27.13+/-7.63)% and the burst frequency (-21.34+/-4.88)%. In addition, the inhibitory effects of CNQX and genistein were the same whether they were applied alone or one after another, indicating that they had no cooperative effects. The results obtained suggest that PTK within the NTS regulates the peripheral chemoreflex control of respiration and that this regulation of PTK may be mediated through the phosphorylation of AMPA receptors in NTS neurons.

Phenomenon of non-associative learning in Hering-Breuer reflex simulated by electrical vagal stimulation in rabbits / 生理学报

The purpose of this study was to explore learning and memory in the Hering-Breuer (HB) reflex simulated by a 60-second-long electrical stimulation of vagus nerve. The responses of phrenic nerve discharge to electrical stimulation (10-100 Hz, 20-60 muA, pulse duration 0.3 ms, for 60 s) of the vagus nerve were observed in rabbits. The results showed that 60-second-long stimulation of vagus nerve produced classic HB reflex, which is composed of two components - lung inflation reflex that is the inhibition of inspiration, and lung deflation reflex that is the facilitation of inspiration. (1) High frequency stimulation (>/=40 Hz, 60 s) of the central end of vagus nerve induced shortening of the inspiratory phase and lengthening of expiratory duration. The inhibitory effect on phrenic discharge was released gradually during sustained vagal stimulation, indicating the habituation of the inhibition. At the cessation of stimulation, the phrenic discharge showed transient post-stimulus rebound. Low frequency stimulation (<40 Hz, 60 s) of the central end of vagus nerve caused an increase in respiratory frequency (f) and shortening of expiratory duration. The excitatory effect on phrenic discharge was also released gradually during the vagal stimulation. The phrenic discharge returned to control level gradually after the removal of the vagal stimulus, indicating short-term potentiation (STP). (2) The habituation of HB reflex was inversely dependent on stimulus intensity and frequency. With an increase in the stimulus frequency or intensity, the degree of the habituation decreased. On the other hand, with the decrease of stimulation intensity and frequency, the degree of the habituation increased. These data indicate a phenomenon of non-associative learning in HB reflex simulated by vagal stimulation. Neural synaptic plasticity and accommodation may exist in the reflex control of respiration in rabbits.

Sustained electrical stimulation of Bötzinger complex on phrenic nerve discharges in rabbits / 中国应用生理学杂志

<p><b>AIM</b>To observe the effects of sustained electrical stimulation at Bötzinger complex (Böt. c) on phrenic nerve discharges.</p><p><b>METHODS</b>Sustained electrical stimulation (10--50 microA, 40-100 Hz, 0.3 ms, for 15-30 s) of Böt. C on 30 urethane anaesthetized, vagotomized, paralyzed and artificially ventilated rabbits.</p><p><b>RESULTS</b>Sustained electrical stimulation of Bot. C produced the inhibition or "inspiratory off-switch" of phrenic discharge during the stimulation. The inhibition of the phrenic discharges showed intensity and frequency dependence. Habituation was shown during the stimulation, showing the magnitude of the phrenic nerve discharge increased gradually. Post-stimulus rebound exhibited upon the cessation of the stimulation, showing the magnitude of the phrenic activity increased significantly. Short-term memory was shown in the habituation of the phrenic activity.</p><p><b>CONCLUSION</b>Non-associative learning is involved in the central control of respiratory modulation in the Böt. C and synaptic plasticity may exist in the respiratory neurons of Böt. C.</p>

The locus coeruleus modulates the inspiratory inhibition induced by electrical stimulation of the Bötzinger complex / 生理学报

Experiments were done on urethane anesthetized adult rabbits. Long-train electrical stimulation was delivered to the Bötzinger complex (Böt.C) to observe the changes in the peak amplitude of integrated phrenic nerve activity. Then, a long-train electrical stimulation was delivered to the locus coeruleus (LC) or monosodium glutamate was microinjected into the LC . Within a certain period of time, another long-train electrical stimulation was delivered to the Böt.C to observe the responses of phrenic nerve activity. We investigated whether the LC could modulate the inspiratory inhibition induced by electrical stimulation of the Böt.C. The results are as follows: (1) Within a certain period of time after a long-train electrical stimulation applied at the LC, the inspiratory inhibition produced by electrical stimulation at the Böt.C was significantly attenuated. Comparing with the control stimulation that was only delivered at Böt.C without pre-stimulation of the LC, the inspiratory inhibition was decreased by (28.78+/-19.49)%. (2) Similarly, after chemical stimulation of the LC with microinjection of monosodium glutamate, the inspiratory inhibition produced by electrical stimulation of Böt.C was also significantly attenuated [decreased by (19.18+/-8.06)%]. The results obtained suggest that the LC plays a role in the modulation of the inspiratory inhibition of Böt.C stimulation.