The rate of quasiparticle recombination probes the onset of coherence in cuprate superconductors.

In the underdoped copper-oxides, high-temperature superconductivity condenses from a nonconventional metallic "pseudogap" phase that exhibits a variety of non-Fermi liquid properties. Recently, it has become clear that a charge density wave (CDW) phase exists within the pseudogap regime. This CDW coexists and competes with superconductivity (SC) below the transition temperature Tc, suggesting that these two orders are intimately related. Here we show that the condensation of the superfluid from this unconventional precursor is reflected in deviations from the predictions of BSC theory regarding the recombination rate of quasiparticles. We report a detailed investigation of the quasiparticle (QP) recombination lifetime, τqp, as a function of temperature and magnetic field in underdoped HgBa2CuO(4+δ) (Hg-1201) and YBa2Cu3O(6+x) (YBCO) single crystals by ultrafast time-resolved reflectivity. We find that τqp(T) exhibits a local maximum in a small temperature window near Tc that is prominent in underdoped samples with coexisting charge order and vanishes with application of a small magnetic field. We explain this unusual, non-BCS behavior by positing that Tc marks a transition from phase-fluctuating SC/CDW composite order above to a SC/CDW condensate below. Our results suggest that the superfluid in underdoped cuprates is a condensate of coherently-mixed particle-particle and particle-hole pairs.

Time-resolved optical reflectivity of the electron-doped Nd(2-x)Ce(x)CuO(4+δ) cuprate superconductor: evidence for an interplay between competing orders.

We use pump-probe spectroscopy to measure the photoinduced reflectivity ΔR of the electron-doped cuprate superconductor Nd(2-x)Ce(x)CuO(4+δ) at a value of x near optimal doping, as a function of time, temperature, and laser fluence. We observe the onset of a negative ΔR signal at T(*)≈75 K, above the superconducting transition temperature, T(c), of 23 K. The relatively slow decay of ΔR, compared to the analogous signal in hole doped compounds, allows us to resolve time-temperature scaling consistent with critical fluctuations. A positive ΔR signal onsets at T(c) that we associate with superconducting order. We find that the two signals are strongly coupled below T(c), in a manner that suggests a repulsive interaction between superconductivity and another fluctuating order.

Observation of coherent helimagnons and gilbert damping in an itinerant magnet.

We study the magnetic excitations of itinerant helimagnets by applying time-resolved optical spectroscopy to Fe(0.8)Co(0.2)Si. Optically excited oscillations of the magnetization in the helical state are found to disperse to lower frequency as the applied magnetic field is increased; the fingerprint of collective modes unique to helimagnets, known as helimagnons. The use of time-resolved spectroscopy allows us to address the fundamental magnetic relaxation processes by directly measuring the Gilbert damping, revealing the versatility of spin dynamics in chiral magnets.

From a single-band metal to a high-temperature superconductor via two thermal phase transitions.

The nature of the pseudogap phase of cuprate high-temperature superconductors is a major unsolved problem in condensed matter physics. We studied the commencement of the pseudogap state at temperature T* using three different techniques (angle-resolved photoemission spectroscopy, polar Kerr effect, and time-resolved reflectivity) on the same optimally doped Bi2201 crystals. We observed the coincident, abrupt onset at T* of a particle-hole asymmetric antinodal gap in the electronic spectrum, a Kerr rotation in the reflected light polarization, and a change in the ultrafast relaxational dynamics, consistent with a phase transition. Upon further cooling, spectroscopic signatures of superconductivity begin to grow close to the superconducting transition temperature (T(c)), entangled in an energy-momentum-dependent manner with the preexisting pseudogap features, ushering in a ground state with coexisting orders.

Unbound plasma concentrations may predict neuroprotective brain concentrations: a brain microdialysis and pharmacokinetic study of enadoline in rats.

A rat brain microdialysis study of enadoline (CI-977), a k-opioid agonist, was conducted in nonanesthetized healthy rats to determine brain extracellular fluid (ECF) concentrations of CI-977 associated with neuroprotective subcutaneous (s.c.) doses. Three groups of 3 to 4 nonanesthetized yet restrained Sprague-Dawley rats with jugular cannulas and implanted brain (striatum) microdialysis probes received single s.c. doses of 0.3, 1.0, or 3.0 mg/kg CI-977. Blood and microdialysate samples were collected over a 12-hour period. Extent of rat plasma protein binding was 77.5%. Unbound plasma concentrations associated with neuroprotection were 10-50 ng eq/mL. At each dose, brain ECF concentration-time profiles (corrected for probe recovery) were nearly coincident with enadoline plasma unbound concentration-time profiles. Consequently, at each dose the ratio of AUCecf/AUCffplasma, (AUC = Area Under the concentration-time Curve; ffplasma = free fraction in plasma = unbound plasma) which represents the distribution of drug between plasma and brain, was determined to be unity within experimental error. These results suggest that unbound plasma concentrations may predict brain ECF concentrations of CI-977. Further, our findings allow us to postulate enadoline unbound brain ECF concentrations necessary for neuroprotection.

Second generation "peptoid" CCK-B receptor antagonists: identification and development of N-(adamantyloxycarbonyl)-alpha-methyl-(R)-tryptophan derivative (CI-1015) with an improved pharmacokinetic profile.

We have previously described the design and development of CI-988, a peptoid analogue of CCK-4 with excellent binding affinity and selectivity for the CCK-B receptor. Due to its anxiolytic profile in animal models of anxiety, this compound was developed as a clinical candidate. However, during its development, it was determined that CI-988 had low bioavailability in both rodent and nonrodent species. In the clinic, it was further established that CI-988 had poor bioavailability. Thus, there was a need to identify an analogue with an improved pharmacokinetic (PK) profile. The poor bioavailability was attributed to poor absorption and efficient hepatic extraction. We envisaged that reducing the molecular weight of the parent compound (5, MW = 614) would lead to better absorption. Thus, we synthesized a series of analogues in which the key alpha-methyltryptophan and adamantyloxycarbonyl moieties, required for receptor binding, were kept intact and the C-terminus was extensively modified. This SAR study led to the identification of tricyclo[3.3.1.1(3,7)]dec-2-yl [1S-[1 alpha(S*)2 beta]-[2-[(2-hydroxycyclohexyl)amino]-1-(1H-indol-3- ylmethyl)-1-methyl-2-oxoethyl]carbamate (CI-1015, 31) with binding affinities of 3.0 and 2900 nM for the CCK-B and CCK-A receptors, respectively. The compound showed CCK-B antagonist profile in the rat ventromedial hypothalamus assay with a Ke of 34 nM. It also showed an anxiolytic like profile orally in a standard anxiety paradigm (X-maze) with a minimum effective dose (MED) of 0.1 microgram/kg. Although the compound is less water soluble than CI-988, oral bioavailability in rat was improved nearly 10 times relative to CI-988 when dosed in HP beta CD. The blood-brain permeability of CI-1015 (31) was also enhanced relative to CI-988 (5). On the basis of the overall improved pharmacokinetic profile as well as enhanced brain penetration, CI-1015 (31) was chosen as a development candidate.

Three complementary liquid chromatographic methods for determination of the peptoid cholecystokinin-B antagonist, CI-988, in rat plasma.

Three different liquid chromatographic methods (two quantitative methods which employ fluorescence detection and one qualitative method which employs selected ion-monitoring detection) were developed and validated to provide complementary specificity for determination of CI-988, a cholecystokinin-B antagonist, in rat plasma. The first quantitative method involves isocratic separation of "non-ionized" CI-988 and internal standard on a C-18 column, whereas the alternative quantitative method involves isocratic separation of the "anionic" analytes. These two quantitative HPLC methods rely on the intrinsic fluorescence of CI-988 and internal standard for detection, and both methods are equally sensitive (linear range of 2.0-1000 ng ml-1), accurate (+/- 15% relative error), and precise (< or = 15% relative standard deviation). Plasma CI-988 concentrations for samples (N = 69) assayed with the "non-ionized" separation are linearly correlated with concentrations for the same samples assayed with the "anionic" separation (y = 1.08 chi - 0.57, R = 0.999). In addition, a third qualitative method, HPLC-thermospray mass spectrometry, was developed to provide complementary evaluation of assay specificity through the use of selected CI-988 fragment ion monitoring. When investigating an anomalous chromatographic result that calls into question the specificity of a method, the availability and use of alternative validated chromatographic separations and orthogonal detection schemes are beneficial.

A sensitive high-performance liquid chromatographic assay for the cholecystokinin-B antagonist, CI-988, in human and monkey plasma.

A sensitive and specific high-performance liquid chromatographic assay for the non-peptide cholecystokinin subtype B receptor antagonist, CI-988, in human and cynomolgus monkey plasma has been developed and validated. The method involves isolation of CI-988 and internal standard by batch robotic solid phase extraction with a C18 cartridge, liquid chromatographic separation on a C18 column and quantitation by fluorescence detection. The human plasma assay is linear from 0.25 to 500 ng/mL for a 1.00-mL plasma aliquot. Assay precision for CI-988 based on human plasma quality control samples was within +/- 7.2% relative standard deviation with an accuracy of +/- 5.6% relative error. The monkey plasma assay is linear from 1.00 to 250 ng/mL for a 0.500-mL plasma aliquot. Assay precision based on monkey plasma quality control samples was within +/- 11.0% relative standard deviation with an accuracy of +/- 2.6% relative error.