Effects of JO 1784, A selective sigma ligand, on the autoradiographic localization of M2 and M2 muscarinic receptor subtypes in trimethyltin treated rats

The distribution patterns of M₁ and M₂ muscarinic receptor subtypes following TMT and JO 1784 administration in the male Sprague-Dawley rat were investigated. In the present study, JO 1784 was injected in doses of 1, 4 and 16 mg/kg i.p. for one week prior to the single injection of TMT (8 mg/kg i.p.) and subsequently for 33 days. The effects of JO 1784 on the density of muscarinic receptor sub-types (M₁ and M₂) in the control and trimethyltin (TMT) treated rats were then evaluated. The topographic distribution and changes in muscarinic (M₁ and M₂) receptor densities were determined by means of autoradiography using [³H]quinuclidinylbenzilate (QNB). Both sub-types of muscarinic receptors contributed to the observed decrease in total muscarinic receptor binding in TMT-treated rats. In control rats, JO 1784 alone decreased M₁ receptor density in the amygdaloid nuclei, basal ganglia, cortex and hippocampus and decreased M₂ receptor density in the amygdaloid nuclei, basal ganglia, cortex, hippocampus, hypothalamus and septal regions. In TMT treated rats, chronic JO 1784 administration has a “neuroprotective effect” on both M₁ and M₂ receptors subtypes. Thus, following chronic administration of JO 1784 to TMT treated rats, both increases and decreases in M₁ receptor density were observed relative to TMT animals. A significant increase in M₁ receptor density was found in the cortex, olfactory regions, septum, thalamus and basal forebrain nuclei. In the hippocampus (CA₂ and CA₃), a significant decrease in M₁ receptor density was observed. In TMT-treated rats, JO 1784 produced a significant increase in M₂ receptor density in several brain regions with the most marked effects occurring in the amygdaloid nuclei, basal ganglia, cortex, hippocampus and hypothalamus. The ability of the selective sigma ligand, JO 1784, to attenuate the loss of muscarinic receptors in TMT treated rats could be of importance in the development of novel neuroprotective drugs.     

Differential activation of protein kinase C isoforms following chemical ischemia in rat cerebral cortex slices

The aim of the current study was to characterize the effects of chemical ischemia and reperfusion at the transductional level in the brain. Protein kinase C isoforms (, β₁, β₂, γ, δ and ) total levels and their distribution in the particulate and cytosolic compartments were investigated in superfused rat cerebral cortex slices: (i) under control conditions; (ii) immediately after a 5-min treatment with 10 mM NaN₃, combined with 2 mM 2-deoxyglucose (chemical ischemia); (iii) 1 h after chemical ischemia (reperfusion). In control samples, all the PKC isoforms were detected; immediately after chemical ischemia, PKC β₁, δ and isoforms total levels (cytosol + particulate) were increased by 2.9, 2.7 and 9.9 times, respectively, while isoform was slightly reduced and γ isoform was no longer detectable. After reperfusion, the changes displayed by , β₁, γ, δ and were maintained and even potentiated, moreover, an increase in β₂ (by 41 ± 12%) total levels became significant. Chemical ischemia-induced a significant translocation to the particulate compartment of PKC isoform, which following reperfusion was found only in the cytosol. PKC β₁ and δ isoforms particulate levels were significantly higher both in ischemic and in reperfused samples than in the controls. Conversely, following reperfusion, PKC β₂ and isoforms displayed a reduction in their particulate to total level ratios. The intracellular calcium chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid, 1 mM, but not the N-methyl-d-asparate receptor antagonist, MK-801, 1 μM, prevented the translocation of β₁ isoform observed during ischemia. Both drugs were effective in counteracting reperfusion-induced changes in β₂ and isoforms, suggesting the involvement of glutamate-induced calcium overload. These findings demonstrate that: (i) PKC isoforms participate differently in neurotoxicity/neuroprotection events; (ii) the changes observed following chemical ischemia are pharmacologically modulable; (iii) the protocol of in vitro chemical ischemia is suitable for drug screening.     

Aromatic analogs of arcaine inhibit MK-801 binding to the NMDA receptor

Aromatic analogs of arcaine were shown to have inhibitory effects on the binding of the channel blocking drug [³H]MK-801 to the NMDA receptor complex. The most potent compound of the series was an N,N′-bis(propyl)guanidinium which inhibited [³H]MK-801 binding with an IC₅₀ of 0.58 μM and an IC₅₀ of 12.17 μM upon addition of 100 μM spermidine. The increase in IC₅₀ upon addition of spermidine suggests competitive antagonism between the inhibitor and spermidine at the arcaine-sensitive polyamine site of the NMDA receptor complex.     

Mode of binding of [3H]dibenzocycloalkenimine (MK-801) to the N-methyl-D-aspartate (NMDA) receptor and its therapeutic implication

Binding of the labeled anticonvulsant drug [³H]dibenzocycloalkenimine (³H]MK-801) to the N-methyl-D-aspartate (NMDA) receptor and its dissociation from the receptor at 25°C are slow processes, both of which follow first order kinetics (t_1/270 and 180 min, respectively). Both reactions are markedly accelerated by glutamate and glycine (t_1/22-8 and 4 min, respectively), which allow bimolecular association kinetics of the labeled drug with the receptors whereas equilibrium binding of [³H]MK-801 (K_d 2–4 nM) is hardly affected by glutamate and glycine. The data suggest that MK-801 acts as a steric blocker of the NMDA receptor channel. The competitive antagonist D-(−)-2-amino-5-phosphovaleric acid (AP-5) freezes the receptor in a state which precludes either binding of [³H]MK-801 to the receptor channel or its dissociation from it. These findings have therapeutic implications.     

Beta(1)/beta(2)/beta(3)-adrenoceptor knockout mice are obese and cold-sensitive but have normal lipolytic responses to fasting

Catecholamines are viewed as major stimulants of diet- and cold-induced thermogenesis and of fasting-induced lipolysis, through the β-adrenoceptors (β₁/β₂/β₃). To test this hypothesis, we generated β₁/β₂/β₃-adrenoceptor triple knockout (TKO) mice and compared them to wild type animals. TKO mice exhibited normophagic obesity and cold-intolerance. Their brown fat had impaired morphology and lacked responses to cold of uncoupling protein-1 expression. In contrast, TKO mice had higher circulating levels of free fatty acids and glycerol at basal and fasted states, suggesting enhanced lipolysis. Hence, β-adrenergic signalling is essential for the resistance to obesity and cold, but not for the lipolytic response to fasting.     

Use of genetically modified mice to examine the skeletal anabolic activity of vitamin D

We employed genetically modified mice to examine the role of 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] on skeletal and calcium homeostasis. In mice expressing the null mutation for 25-hydroxyvitamin D 1 hydroxylase (1OHase^−/−), or the vitamin D receptor (VDR^−/−), 1,25(OH)₂D₃ and calcium were both required for optimal epiphyseal growth plate development, serum calcium and phosphorus alone were sufficient to mineralize skeletal tissue independent of 1,25(OH)₂D₃ and the VDR, and endogenous 1,25(OH)₂D₃ and the VDR were essential for baseline bone formation. In 2-week-old 1OHase^−/− mice and in 2-week-old mice homozygous for the PTH null mutation(PTH^−/−), PTH and 1,25(OH)₂D₃ were each found to exert independent and complementary effects on skeletal anabolism, with PTH predominantly affecting appositional trabecular bone growth and 1,25(OH)₂D₃ influencing both endochondral bone formation and appositional bone growth. Endogenous 1,25(OH)₂D₃ maintained serum calcium homeostasis predominantly by modifying intestinal and renal calcium transporters but not by producing net bone resorption. Administration of exogenous 1,25(OH)₂D₃ to double mutant PTH^−/−1OHase^−/− mice produced skeletal effects consistent with the actions of endogenous 1,25(OH)₂D₃. These studies reveal an important skeletal anabolic role for both endogenous and exogenous 1,25(OH)₂D₃ and point to a potential role for 1,25(OH)₂D₃ analogs in the treatment of disorders of bone loss.     

Synthesis, structure, and heterogeneous catalytic activity of tungsten chalcogenide cubane cluster containing alkaline earth metal complex

A new compound containing a cubane tungsten chalcogenide cluster [W₄(μ₃-Te)₄(CN)₁₂]⁶⁻ and Ca²⁺ complex units has been prepared by the reaction of aqueous solution of K₆[W₄(μ₃-Te)₄(CN)₁₂] · 5H₂O with the solution of a Ca(NO₃)₂ and phen(1,10-phenanthroline) (1:2 molar ratio) in a solvent mixture of H₂O/EtOH. The structure of [{Ca(phen)₂(H₂O)}{Ca(phen)(H₂O)₄}{Ca(phen)₂(H₂O)₃}][W₄Te₄(CN)₁₂] · 5H₂O 1 has been determined by X-ray crystallography. Compound 1 contains [{Ca(phen)(H₂O)₄}{Ca(phen)₂(H₂O)₃}][W₄(μ₃- Te)₄(CN)₁₂] units bridged by {Ca(phen)₂(H₂O)}²⁺ units to form an one-dimensional zigzag chain structure. Interestingly, compound 1 showed a heterogeneous catalytic activity in the transesterification of a range of esters with methanol under the mild conditions. Moreover, it can be reused without any loss of activity through 10 runs with ester.     

8-OH-DPAT and MK-801 affect epileptic activity independently of vigilance

Vigilance and parallel occurrence of epileptic activity after administration of the 5-HT_1A agonist 8-OH-DPAT and the NMDA receptor antagonist MK-801 were studied in the genetic absence epilepsy model WAG/Rij rats. Spike-wave discharges (SWD) were present predominantly in passive awake and light slow wave sleep (SWS1) either in control animals or after treatments. Injection of 8-OH-DPAT (20.0 μg/rat i.c.v.) caused marked increase and MK-801 (10.0 μg/rat i.c.v.) decrease in SWD densities, thus the ratios of SWD in passive awake and in SWS1. SWD densities of MK-801 plus 8-OH-DPAT in combination were similar to those of CSF+CSF treated control rats. Both 8-OH-DPAT and MK-801 transiently increased the duration of active awake, increased latency and decreased duration of rapid eye movement (REM) sleep. 8-OH-DPAT increased the amount of SWD despite the decrease in the duration of SWS1. MK-801 decreased the amount of SWD despite the lack of significant change in duration of passive awake or SWS1. Pre-treatment with MK-801 reversed 8-OH-DPAT- induced increase in duration of SWD without any effect on 8-OH-DPAT-induced changes in sleep parameters. Our studies provide evidence that 8-OH-DPAT-induced epileptic activity is independent of its effect on sleep, and that interaction of serotonergic and glutamatergic systems plays a role in the generation of SWD, but not in the regulation of vigilance and sleep.     

Synthesis, immobilization and catalytic activity of some silylated cyclopentadienyl rhodium(I) complexes

The mixture of isomers of silylated cyclopentadiene derivative C₅H₅CH₂CH₂Si(OMe)₃ (1) has been used for the syntheses of the mononuclear Rh(I) complexes [η⁵-C₅H₄(CH₂)₂Si(OMe)₃]Rh(CO)₂ (3). [η⁵-C₅H₄(CH₂)₂Si(OMe)₃]Rh(COD) (4) and [η⁵-C₅H₄(CH₂)₂Si(OMe)₃]Rh(CO)(PPh₃) (5). Upon entrapment of 3–5 in silica sol-gel matrices, air stable, leach-proof and recyclable catalysts 6–8 resulted. Their catalytic activities in some hydrogenation processes were compared with those of the non-immobilized complexes 3–5, as well as with those of homogeneous and heterogenized non-silylated analogs, 9–14.     

Pharmacological Characterization of Heterodimeric NMDA Receptors Composed of NR 1a and 2B Subunits: Differences with Receptors Formed from NR 1a and 2A

Abstract: Pharmacological and molecular biological evidence indicates the existence of multiple types of NMDA receptors within the CNS. We have characterized pharmacological properties of receptors assembled from the combination of NR 1a and NR 2B subunits (NR 1a/2B) expressed in transfected cells using both ¹²⁵I-MK-801 binding assays and electrophysiological measures. Binding of ¹²⁵I-MK-801 to cells transfected with NR 1a/2B is saturable with a K _D of 440 p M . The binding is potently inhibited by ketamine, dextromethorphan, phencyclidine, and MK-801 and is stimulated by low concentrations of magnesium. These properties resemble those of native receptors and receptors produced by NR 1a/2A. However, ¹²⁵I-MK-801 binding to membranes from cells transfected with NR 1a/2B is inhibited with high affinity by ifenprodil and is stimulated by spermidine, unlike receptors assembled from NR 1a/2A. NMDA-induced currents measured in cells transfected with either NR 1a/2A or NR 1a/2B have pharmacological properties that correlate well with the binding studies. Currents in cells transfected with NR 1a/2B are potentiated by spermidine and blocked with high affinity by ifenprodil, whereas currents in cells transfected with NR 1a/2A are not enhanced by spermidine and are weakly inhibited by ifenprodil. These data suggest that pharmacological heterogeneity in native NMDA receptors may be explained by combinations of different subunits.     

Mono-η complexes of chromium(II) and chromium(0). Electron demanding substituents, structural and spectroscopic data comparisons

Using thermal and photochemical methods a series of new chromium complexes has been prepared: (ν⁶-p-C₆H₄F₂)Cr(CO)₃; (ν⁶-C₆H₅CF₃)Cr(CO)₃; [m-C₆H₄(CF₃)₂]Cr(CO)₃; (ν⁶-C₆H₅F)Cr(CO)₂H(SiCl₃); (ν⁶-C₆H₅F)Cr(CO)₂(SiCl₃)₂; (p-C₆H₄F₂)Cr(CO)₂-H(SiCl₃); (C₆H₅CF₃)Cr(CO)₂H(SiCl₃(p-C₆H₄F₂)Cr(CO)₂(SiCl₃)₂; C₆H₅CF₃)Cr(CO)₂(SiCl₃)₂; [m-C₆H₄(CF₃)₂]Cr(CO)₂-H(SiCl₃); [m-C₆H₄(CF₃)₂]Cr(CO)₂(SiCl₃)₂. Two compounds were structurally characterized by X-ray diffraction. These data combined with IR and ¹H NMR have allowed assessment of some of the electronic and steric effects. The Cr-arene bond is considerably longer in the Cr(II) derivatives than in the Cr(0) species. Also the Cr center, as might be expected, is less electron rich in the Cr(II) dicarbonyl disilyl derivatives. The ν⁶-p-C₆H₄F₂ ligands are slightly folded so that the C---F carbons are moved further away from the Cr center. Comparison of structural and electronic effects is made with a series of similar chromium compounds reported in the literature. These new (arene)Cr(II) derivatives possess more labile ν⁶-arene ligands, which promise a rich chemistry at the chromium center.     

Chemistry of vinylidene complexes XI. Synthesis of trinuclear MnFePt complexes by means of consecutive assembling out of mono- and dimetal vinylidene precursors

The dimetal μ-vinylidene complexes Cp(CO)₂MnPt(μ-C = CHPh)L₂ (L = tert.-phosphine or -phosphite), which have been obtained by coupling of the mononuclear complex Cp(CO)₂Mn=C=CHPh and unsaturated PtL₂ unit, add smoothly the Fe(CO)₄ moiety to produce trimetal MnFePt compounds. The μ₃-vinylidene cluster CpMnFePt(μ₃-C=CHPh)(CO)₆(PPh₃) was prepared in quantitative yields from the reactions of Cp(CO)₂MnPt(μ-C=CHPh)(PPh₃)L (L = PPh₃ or CO) with Fe₂(CO)₉ in benzene at 20 °C. The phosphite-substituted complexes Cp(CO)₂Mnpt(μ-C=CHPh)L₂ (L = P(OEt)₃ or P(OPrⁱ)₃) react under analogous conditions with Fe₂(CO)₉ to give mixtures (2:3) of the penta- and hexacarbonyl clusters, CpMnFePt(μ₃-C = CHPh)(CO)₅L₂ and CpMnFePt(μ₃-C = CHPh)(CO)₆L, respectively. The similar reaction of the dimetal complex Cp(CO)₂MnPt(μ-C = CHPh)(dppm), in which the Pt atom is chelated by dppm = Ph₂PCH₂PPhPin2 ligand, gives only a 15% yield of the analogous trimetal μ₃-vinylidene hexacarbonyl product CpMnFePt(μ₃-C = CHPh)(CO)(dppm), but the major product (40%) is the tetranuclear μ₄-vinylidene cluster (dppm)PtFe₃(μ₄-C = CHPh)(CO)₉. The IR and ¹H, ¹³C and ³¹P NMR data for the new complexes are reported and discussed.     

Cis- and trans-titanium complexes with doubly silyl-bridged dicyclopentadienyl ligands: molecular structure of [(TiCl)2(μ-O){(SiMe2)2(η-C5H3)2}]2(μ-O)2

The reaction of TiCl₄ with Li₂[(SiMe₂)₂(η⁵-C₅H₃)₂] in toluene at room temperature afforded a mixture of cis- and trans-[(TiCl₃)₂{(SiMe₂)₂(η⁵-C₅H₃)₂}] in a molar ratio of 1/2 after recrystallization. The complex trans-[(TiCl₃)₂{(SiMe₂)₂(η⁵-C₅H₃)₂}] was hydrolyzed immediately by the addition of water to THF solutions to give trans-[(TiCl₂)₂(μ-O){(SiMe₂)₂(η⁵-C₅H₃)₂}] as a solid insoluble in all organic solvents, whereas hydrolysis of cis-[(TiCl₃)₂{(SiMe₂)₂(η⁵-C₅H₃)₂}] under different conditions led to the dinuclear μ-oxo complex cis-[(TiCl₂)₂)(μ-O){(SiMe₂)₂(η⁵-C₅H₃)₂}] and two oxo complexes of the same stoichiometry [(TiCl)₂(μ-O){(SiMe₂)₂(η⁵-C₅H₃)₂}]₂(μ-O)₂ as crystalline solids. Alkylation of cis- and trans-[(TiCl₃)₂{(SiMe₂)₂(η⁵-C₅H₃)₂}] with MgCIMe led respectively to the partially alkylated cis-[(TiMe₂Cl)₂{(SiMe₂)₂(η⁵-C₅H₃)₂}] and the totally alkylated trans-[(TiMe₃)₂{(SiMe₂)₂(η⁵-C₅H₃)₂}] compounds. The crystal and molecular structure of the tetranuclear oxo complex [(TiCl)₂(μ-O){(SiMe₂)₂(η⁵-C₅H₃)₂}]₂(μ-O)₂ was determined by X-ray diffraction.     

Preparation, structure and properties of triphenylphosphine rhodium aryloxides

The reaction of Wilkinson's catalyst with NaOAr in toluene cleanly affords the corresponding aryloxide complexes Rh(PPh₃)₃OAr (1). In solution, 1 exists in equilibrium with PPh₃ and the corresponding Rh(PPh₃)₂(π-ArO) (2). The addition of HOAr shifts the equilibrium completely toward the corresponding adducts 2·2HOAr, due to hydrogen bonding between the oxygen atom of the π-coordinated OAr ligand and two molecules of HOAr. Heating of 1a-d in toluene at 60–80°C leads to the elimination of HOAr with concomitant cyclometallation of a phenyl ring of one PPh₃ ligand, affording mixtures of 1,2·2HOAr, a cyclometallated Rh complex and PPh₃. At room temperature, a reverse reaction slowly occurs to give equilibrium mixtures of 1, 2 and PPh₃. Complexes 1 readily with water, CO and H₂, affording Rh₂(PPh₃)₄(μ-OH)₂, Rh(PPh₃)₂(CO)OAr (3) and HRh(PPh₃)₃, respectively. The latter complex was also obtained when complexes 1 were treated with methanol. The structures of the phenoxide complexes 1 and 2·2PhOH and of p-nitrophenoxide complex 3 were established by X-ray diffraction.     

Organometallic chemistry of diphosphazanes. Rhodium(I) complexes of RN(PX2)2 (R = C6H5; X = OC6H5, OC6H4Br−p, R = CH3; X = OC6H5)

Reactions of [Rh(COD)Cl]₂ with the ligand RN(PX₂)₂ (1: R = C₆H₅; X = OC₆H₅) give mono- or disubstituted complexes of the type [Rh₂(COD)Cl₂{ν²−C₆H₅N(P(OC₆H₅)₂)₂}] or [RhCl{ν²−C₆H₅ N(P(OC₆H₅)₂)₂ }]₂ depending on the reaction conditions. Reaction of 1 with [Rh(CO)₂Cl]₂ gives the symmetric binuclear complex, [Rh(CO)Cl{μ−C₆H₅N(P(OC₆H₅)₂)₂} ₂, whereas the same reaction with 2 (R = CH₃; X = OC₆H₅) leads to the formation of an asymmetric complex of the type [Rh(CO)(μ−CO)Cl{μ−CH₃N(P(OC₆H₅)₂)₂}₂ containing both terminal and bridging CO groups. Interestingly the reaction of 3 (R = C₆H₅, X = OC₆H₄Br−p with either [Rh(COD)Cl]₂ or [Rh(CO)₂Cl]₂ leads only to the formation of the chlorine bridged binuclear complex, [RhCl{ν²−C₆H₅N(P(OC₆H₄Br−p)₂)₂}]₂. The structural elucidation of the complexes was carried out by elemental analyses, IR and ³¹P NMR spectroscopic data.     

The new enneanuclear nickel carbonyl anion [Ni9(CO)16] and its relationships with the [Ni12(CO)21] and [Ni6Rh3(CO)17] clusters

The reaction of [N(PPh₃)₂]₂[Ni₆(CO)₁₂] with Cu(PPh₃)_xCl (x=1, 2), as well as the degradation of [N(PPh₃)₂]₂[H₂Ni₁₂(CO)₂₁] with PPh₃, affords the new and unstable dark orange–brown [N(PPh₃)₂]₂[Ni₉(CO)₁₆].THF salt in low yields. This salt has been characterized by a CCD X-ray diffraction determination, along with IR spectroscopy and elemental analysis. The close-packed two-layer metal core geometry of the [Ni₉(CO)₁₆]²⁻ dianion is directly related to that of the bimetallic [Ni₆Rh₃(CO)₁₇]³⁻ trianion and may be envisioned to be formally derived from the hcp three-layer geometry of [Ni₁₂(CO)₂₁]⁴⁻ by the substitution of one of the two outer [Ni₃(CO)₃(μ−CO)₃]²⁻ layers with a face-bridging carbonyl group.     

Mixed-metal butterfly acetamidediato clusters derived from a highly reactive ruthenium oxo cluster: synthesis and characterization of [(PPh3)2N][MRu3(CO)12(η-μ3-NC(μ-O)CH3)], (M = Mn or Re)

Analogy with the isolable oxo cluster [Fe₃(CO)₉(μ₃-O)]²⁻, which is structurally interesting and synthetically useful, prompted the present attempt to synthesize its ruthenium analog. Although the high reactivity of [Ru₃(CO)₉(μ₃-O)]²⁻ (I) prevented its isolation, the reaction of this species with [M(CO)₃(NCCH₃)]⁺, where M = Mn or Re, yields [PPN][MRu₃(CO)₁₂(η²-μ₃-NC(μ-O)CH₃]⁻. The high nucleophilicity of the oxo ligand in [Ru₃(CO)₉(μ₃-O)]²⁻ (I) appears to be responsible for the conversion of acetonitrile to an acetamidediato ligand and for the instability of I. The crystal structure of [PPN][MnRu₃(CO)₁₂(η²-μ₃-NC(μ-O)CH₃)]] reveals a hinged butterfly array of metal atoms in which the acetamidediato ligand bridges the two wings with μ₃-N bonding to an Mn and two Ru atoms, and μ-O bonding to an Ru atom.     

Manganese(II) complexes of an acyclic phenol-based dinucleating ligand with four methoxyethyl chelating arms: synthesis, structure, magnetism and electrochemistry

Dinuclear manganese(II) complexes [Mn₂(bomp)(PhCO₂)₂]BPh₄ (1), [Mn₂(bomp)(MeCO₂)₂]BPh₄ (2), and [Mn₂(bomp)(PhCO₂)₂]PF₆ (3) were synthesized with a dinucleating ligand 2,6-bis[bis(2-methoxyethyl)aminomethyl]-4-methylphenol [H(bomp)]. Dinuclear zinc complex [Zn₂(bomp)(PhCO₂)₂]PF₆ (4) was also synthesized for the purpose of comparison. X-ray analysis revealed that the complex 1·CHCl₃ contains two manganese ions bridged by the phenolic oxygen and two benzoate groups, forming a μ-phenoxo-bis(μ-benzoato)dimanganese(II) core. Magnetic susceptibility measurements of 1–3 over the temperature range 1.8–300 K indicated antiferromagnetic interaction (J=−4 to −6 cm⁻¹). Cyclic voltammograms of 3 showed a quasi-reversible oxidation process at +0.9 V versus a saturated sodium chloride calomel reference electrode, assigned to Mn^IIMn^II/Mn^IIMn^III.     

Beta(3)-adrenoceptor agonists for the treatment of frequent urination and urinary incontinence: 2-[4-(2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl)phenoxy]-2-methylpropionic acid.

In a search for novel analogues of β₃-adrenoceptor (AR) agonists relaxing the bladder for treatment of urinary dysfunction, 2-[4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)phenoxy]-2-methylpropionic acids (1a–e), into which a fibrate-like structure had been incorporated, were synthesised. Compound 1a was found to be a selective β₃-AR agonist in functional assays using the ferret detrusor (β₃-AR), rat uterus (β₂-AR), and rat atrium (β₁-AR); β₃: EC₅₀=7.8 nM, β₂: IC₅₀=7,300 nM, β₁: EC₂₀=23,000 nM. The introduction of a chlorine atom or methyl substituent at the ortho-position on the phenyl ring of 1a further improved β₃-AR selectivity. In an in vivo study, 1a lowered intrabladder pressure (ED₅₀=31 μg/kg) in rats, without increasing heart rate, in keeping with the in vitro results. Consequently, it is proposed that 1a and its analogues (1b–e), possess β₃-AR agonistic activity in the absence of undesirable β₁- or β₂-AR mediated actions, and may be useful for clinical treatment and pharmacological studies.     

Anti-β1 Integrin IgG Inhibits Pulmonary Macrometastasis and the Size of Micrometastases from a Murine Mammary Carcinoma

In the present report, we investigated the possible importance of β₁ integrins in the growth and metastasis of a murine mammary carcinoma, SP1, and a metastatic variant, SP1-3M in vivo. CBA/J female mice bearing SP1 tumor transplants were injected with anti-β₁ integrin IgG or control nonimmune IgG (200 μg per mouse; i.p.) every two days. Animals received anti-CD4 antibody (100 μg per mouse) at time zero to suppress immunity against rabbit IgG. Outgrowth of macroscopic metastases from SP1, but not from SP1-3M primary tumors, was markedly inhibited in animals receiving anti-β₁ integrin IgG but not nonimmune IgG. To assess the stage(s) in the metastatic cascade affected, we examined the number and diameter of micrometastatic nodules in treated and untreated groups. The diameter of micrometastases was significantly reduced in SP1-tumor-bearing mice treated with anti-β₁ integrin IgG compared to control IgG, although the number of nodules per cm² of lung sections examined remained unchanged. No change in the number or size of micrometastases in SP1-3M tumor-bearing mice was observed. No difference in the binding, or complement-mediated and antibody-dependent cell-mediated cytotoxicity of anti-β₁ integrin IgG with SP1 and SP1-3M cells was detected. The results suggest that under these conditions anti-β₁ integrin inhibits metastatic tumor growth in lung tissue, but has minimal effect on intravasation, adhesion to target organs and extravasation.