-084, a aselectivePCPderivative, attenuates MK-8Ol-induced impairment of learning in mice. PHARMACOL BIOCHEM BEHAV 49(4) [859][860][861][862][863][864][865][866][867][868][869] 1994.-We investigated the effect of the tr selective PCP derivative PRE-084 on the impairment of learning induced in mice by the noncompetitive NMDA antagonist MK-801. Learning capacities were evaluated using the spontaneous alternation in a Y-maze test for spatial working memory, the step-down passive avoidance and the elevated plus-maze test for long-term memory. At doses about 1 mg/kg IP, PRE-084 significantly attenuated MK-801 (0.2 mg/kg IP) induced impairment of learning. The dose-response curve was bell-shaped which is typical for cognition enhancers. The effect of PRE-084 was antagonized by BMY-14802 (10 mg/kg IP) and suppressed by a chronic treatment with haloperidol (4 mg/kg/day SC for 7 days). Furthermore, PRE-084 did not affect scopolamine (1 mg/kg SC) induced amnesia but significantly attenuated mecamylamine (10 mg/kg IP) induced amnesia. These results show that a sites mediate a modulation of the NMDA receptor complex-dependent learning processes and may similarly affect the cholinergic nicotinic memory processes. Moreover, the PCP derivative PRE-084, acting selectively at a sites, reverses the amnesia induced by a drug acting at the PCP site. , and dextrometorphan bind with a high affinity and stereoselectivity, and the a2 site, which has lower affinity and is not stereoselective for these ligands. Both 1,3-di-(2-tolyl)guanidine (DTG) and haloperidol are nonselective drugs and bind with a similar high affinity to the two classes of sites (25,34,42). Further, it has been shown that haloperidol, rimcazole, o~-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol (BMY-14802) and N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)-ethylamine hydrochloride (NE-100) appear to act as antagonists in several behavioralTo whom request for reprints should be addressed.tests (23,35,36). On the other hand, it is now clear that these sites are different entities from opiate receptors, for which they were initially classified, and from the high affinity phencyclidine (PCP) binding site (26). The PCP site is located inside the ion channel associated with the N-methyl-Daspartate (NMDA) type of glutamate receptor. Drugs, such as PCP, its more selective derivative TCP, or MK-801, bind with high affinity to this site and lead to a noncompetitive antagonism of the NMDA type of glutamatergic neurotransmission (1,18).Although the pharmacological roles of cr sites are not yet well understood, evidences indicate that they may have several biological functions (32,41). Among them, a facilitatory role 859
The 1H NMR characteristics of the high-spin metmyoglobin from the mollusc Aplysia limacina have been investigated and compared with those of the myoglobin (Mb) from sperm whale. Aplysia metMb exhibits a normal acid----alkaline transition with pK approximately 7.8. In the acidic form, the heme methyl and meso proton resonances have been assigned by 1H NMR using samples reconstituted with selectively deuterated hemins and in the latter case by 2H NMR as well. On the basis of the methyl peak intensities and shift pattern, heme rotational disorder could be established in Aplysia Mb; approximately 20% of the protein exhibits a reversed heme orientation compared to that found in single crystals. Three meso proton resonances have been detected in the upfield region between -16 and -35 ppm, showing that the chemical shift of such protons can serve as a diagnostic probe for a pentacoordinated active site in hemoproteins, as previously shown to be the case in model compounds. The temperature dependence of the chemical shift of the meso proton signals deviates strongly from the T-1 Curie behavior, reflecting the presence of a thermally accessible Kramers doublet with significant S = 3/2 character. Nuclear Overhauser effect, NOE, measurements on Aplysia metMb have provided the assignment of individual heme alpha-propionate resonances and were used to infer spatial proximity among heme side chains. The hyperfine shift values for assigned resonances, the NOE connectivities, and the NOE magnitudes were combined to reach a qualitative picture of the rotational mobility and the orientation of the vinyl and propionate side chains of Aplysia metMb relative to sperm whale MbH2O.(ABSTRACT TRUNCATED AT 250 WORDS)
The monomeric insect (Chironomus thummi thummi) haemoglobins CTT 111 and CTT IV show an alkaline Bohr effect. The amplitude of the Bohr effect curve of CTT IV is about twice as large as that of CTT 111. In particular, at low pH a time-dependent 'slow' decrease in p s o upon cyclic oxygenation/deoxygenation is observed which is larger if dithionite, instead of ascorbate, is the reducing agent. The decrease of p s o (increase in affinity) correlates with the ratio of haem-rotational components exhibiting an increase of the 'myoglobin-like' haemrotational component with high O2 affinity and high stability of the globin-haem complex.The replacement of protohaem IX by mesohaem IX and deuterohaem IX, respectively, causes an increase in O2 affinity following the order: proto < meso < deutero CTT Hbs. The Bohr effect, however, seems not to be affected by these porphyrin side-group substitutions. The O2 affinity is modulated by steric effects due to the substituents in position 2 and 4 via variation of the protein-haem interactions which influence the O2 release.The replacement of iron by cobalt in proto and meso CTT IV leads to an increase of the p.30 by two to three orders of magnitude. Neither central metal nor vinyl replacement affect the Bohr effect.The natural CTT Hbs 111 and IV analyzed for mono-componential kinetic systems exhibit pH-dependent O2 off-rate constants: 300 s-' (at pH 5.6) and 125 s-l (at pH 9.7) for CTT 111, and 550 s-l (at pH 5.4) and 100 s-' (at pH 9.0) for CTT IV. Inflection points and amplitudes of the log koff/pH plots correspond to those obtained from the Bohr effect curves indicating again a larger Bohr effect for CTT IV than for CTT 111. In contrast, the O2 on-rate constants are pH-independent (Icon = 1.15 -1.26 x lo8 M-' s-l). Thus, the Bohr effect is completely controlled by the off-rate constants.Analysis for bi-componential kinetic systems employing the eigenfunction expansion method clearly identifies two kinetic components for proto-IX and deutero-IX CTT Hbs which can be attributed to the two haem-rotational components x and y ( x and y differ due to an 180" rotation of the haem group about the qy-meso axis; y is the The monomeric insect haemoglobins CTT I11 and CTT IV exhibit a Bohr effect [l -31 and therefore serve as simple allosteric model systems [4, 51. Changes in ligation or in pH have no effect on the molecular mass of these haemoglobins which are therefore monomeric under all conditions [2, 61. The pH-dependent ligand afinity is controlled by a single proton (Bohr proton) [2,3,7 -91. NMR titration experiments [7] and histidine assignments based on X-ray structure analysis [lo] provided evidence that the allosteric site in CTT 111 (Bohr proton binding site) is a salt bridge formed by the imidazole group of His-G2 and the C-terminal carboxyhc group of Met-H22. At low pH, this salt bridge stabilizes the tense tertiary structure (t state) characterized by low O2 affinity. At high pH, by dissociation of the Bohr proton, the salt bridge is opened leading to a transition of the terti...
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