Disease relevance of N-ethyl-1,2-dimethyl-6-methylimino-N-phenyl-pyrimidin-4-amine

• We hypothesized that peripheral block of I h on axons would produce an antiallodynic effect in postoperative as well as neuropathic conditions, and we tested perineural administration of ZD 7288, a specific blocker of I h , on pain-associated behavior in animal models of neuropathic and postoperative pain [1].

High impact information on N-ethyl-1,2-dimethyl-6-methylimino-N-phenyl-pyrimidin-4-amine

• ZD 7288 increased the current threshold for evoking antidromic action potentials by extracellular stimulation, consistent with the expression of Ih in BC axons [2].
• ZD 7288 blocked a hyperpolarization-activated current in a concentration-dependent manner (IC50, 1.4 microm) [2].
• Inhibition of I(h) by 10 microM ZD 7288 reduced the frequency ( approximately 34 %) and amplitude ( approximately 26 %) of spontaneous IPSCs (sIPSCs) recorded in Purkinje cells, one of the principal synaptic targets of basket neurones [3].
• 5. The co-application of ZD 7288 and Ba2+ revealed a depolarizing sag in negative voltage deviations under current clamp conditions, or a large inward current with kinetics two to three times slower than those of Ih under voltage clamp conditions [4].
• There was no additive effect when ZD 7288 and clonidine were combined, and a decreased duration of nerve block when either forskolin or 8-Br-cAMP preceded injection of lidocaine with clonidine [5].

Biological context of N-ethyl-1,2-dimethyl-6-methylimino-N-phenyl-pyrimidin-4-amine

• Furthermore, ZD 7288 blocked both forskolin- and Sp-8-CPT-cAMPS-mediated enhancements of synaptic transmission [6].
• Interestingly, these neurons exhibited a voltage-dependent membrane resonance (<10 Hz) that was prominent around resting potential and more negative to rest and was blocked by ZD 7288 [7].
• 1. ZENECA ZD7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride, formerly ICI D7288) is a novel sino-atrial node function modulator which selectively slows heart rate [8].
• The role of the hyperpolarization-activated cation current (Ih) was evaluated by injecting the current blocker ZD 7288 as well as the current enhancers forskolin and 8-Br-cAMP before lidocaine alone or with 15 micrograms/ml clonidine [5].

Anatomical context of N-ethyl-1,2-dimethyl-6-methylimino-N-phenyl-pyrimidin-4-amine

• The properties of these currents, such as steady-state variables, dependence on external K, modification by norepinephrine, and blockade by Cs or ZD-7288, coincide well with those of the "classical" I(h) discovered in the sinoatrial node [9].
• The hyperpolarizing effect of ZD 7288 was also substantially larger in interneurons clamped near -80 mV using current injection through the pipette [10].
• Mechanism of block by ZD 7288 of the hyperpolarization-activated inward rectifying current in guinea pig substantia nigra neurons in vitro [11].
• ZD-7288 (0.1-10 microM) inhibited a current that reversed at -43.7+/-3.7 mV in artificial cerebrospinal fluid (ACSF) containing 3 mM K(+) (n=9), and displayed the time and voltage dependence of the hyperpolarisation-activated current, I(h) [12].
• The bradycardic agent ZD-7288 (10 microM), a selective inhibitor of I(h), produced a characteristically slow inhibition of the portal vein I(h) [13].

Associations of N-ethyl-1,2-dimethyl-6-methylimino-N-phenyl-pyrimidin-4-amine with other chemical compounds

• In contrast, ZD-7288, a specific I(h) blocker, did not cause spontaneous epileptiform activity in CA1 and CA3, nor did it affect the field bursts in the dentate gyrus, suggesting that cesium induced epileptiform activity is not directly related to blockade of the I(h) [14].
• The pharmacological properties of hHCN1-mediated currents resembled those of native hyperpolarization-activated currents (I(h)), that is, blockade by Cs(+) (99% at 5 mm), ZD 7288 (98% at 100 microm) and zatebradine (92% at 10 microm) [15].
• In addition, three investigational compounds having analgesic potential were examined: ZD-7288, a blocker of HCN channels; EAA-090, an NMDA antagonist; and WAY-132983, a muscarinic agonist [16].
• Effects of Zeneca ZD7288 in comparison with alinidine and UL-FS 49 on guinea pig sinoatrial node and ventricular action potentials [17].
• Cs and ZD 7288 increased the frequency of pacemaker bursts and decreased the frequency of action potentials between pacemaker bursts [18].

Gene context of N-ethyl-1,2-dimethyl-6-methylimino-N-phenyl-pyrimidin-4-amine

• Extracellular application of 70 microM ZD 7288 completely inhibited NMU-induced depolarization [19].
• In addition, ZD 7288 attenuated the amplitude of both AMPA and NMDA receptor-mediated excitatory postsynaptic currents (EPSCs) equally and caused a coincident increase in the failure rate of single-fiber EPSCs and paired-pulse facilitation (PPF) [6].

Analytical, diagnostic and therapeutic context of N-ethyl-1,2-dimethyl-6-methylimino-N-phenyl-pyrimidin-4-amine

• Whole-cell recordings from basket cell somata also revealed an I(h) current, which was similarly sensitive to block by ZD 7288 [3].
• Intravenous injection of ZD 7288, a new specific hyperpolarizing current blocker, dose-dependently reduces heart rate in adult rats [20].

References