Duncan McArthur

Structure–activity studies of a novel series of isoxazole-3-carboxamide derivatives as TRPV1 antagonists

Optimisation of a screening hit incorporating both TRPV1 activity and solubility was conducted. Substitution of the isoxazole-3-carboxamide with the bespoke 1S, 3R-3-aminocyclohexanol motif afforded the requisite balance of potency and solubility. Compounds 32 and 40 were found to have antihyperalgesic effects in the rat CFA Hg assay and induce a mechanism based hyperthermia.

Plasmon modes in single gold nanodiscs

Optical properties of single gold nanodiscs were studied by scanning near-field optical microscopy. Near-field transmission spectra of a single nanodisc exhibited multiple plasmon resonances in the visible to near-infrared region. Near-field transmission images observed at these resonance wavelengths show wavy spatial features depending on the wavelength of observation. To clarify physical pictures of the images, theoretical simulations based on spatial correlation between electromagnetic fundamental modes inside and outside of the disc were performed. Simulated images reproduced the observed spatial structures excited in the disc. Mode-analysis of the simulated images indicates that the spatial features observed in the transmission images originate mainly from a few fundamental plasmon modes of the disc.

Design, synthesis, and structure–activity relationships of indole-3-heterocycles as agonists of the CB1 receptor

Novel indole-3-heterocycles were designed and synthesized and found to be potent CB1 receptor agonists. Starting from a microsomally unstable lead 1, a bioisostere approach replacing a piperazine amide was undertaken. This was found to be a good strategy for improving stability both in vitro and in vivo. This led to the discovery of 24, which had an increased duration of action in the mouse tail flick test in comparison to the lead 1.

Discovery of potent, soluble and orally active TRPV1 antagonists. Structure-activity relationships of a series of isoxazoles.

Systematic optimisation of a poorly soluble lead series of isoxazole-3-carboxamides was conducted. Substitution of the 4-position with specific polar functionality afforded the requisite balance of potency, solubility and physicochemical properties. Compound 21a was found to be efficacious in the rat Capsaicin Hargreaves assay following oral administration.

Identification of potent, soluble, and orally active TRPV1 antagonists

Optimization of a water soluble, moderately potent lead series of isoxazole-3-carboxamides was conducted, affording a compound with the requisite balance of potency, solubility and physicochemical properties for in vivo use. Compound 8e was demonstrated to be efficacious in a rat model of inflammatory pain, following oral administration.

Coherent control of radiation patterns of nonlinear multiphoton processes in nanoparticles

We propose a scheme for the coherent control of light waves and currents in metallic nanospheres which applies independently of the nonlinear multiphoton processes at the origin of waves and currents. We derive conditions on the external control field which enable us to change the radiation pattern and suppress radiative losses or to reduce absorption, enabling the particle to behave as a perfect scatterer or as a perfect absorber. The control introduces narrow features in the response of the particles that result in high sensitivity to small variations in the local environment, including subwavelength spatial shifts.

Evaluation of E. M. fields and energy transport in metallic nanoparticles with near field excitation

We compare two ways of calculating the optical response of metallic nanoparticles illuminated by near field dipole sources. We develop tests to determine the accuracy of the calculations of internal and scattered fields of metallic nanoparticles at the boundary of the particles and in the far field. We verify the correct transport of energy by checking that the evaluation of the energy flux agrees at the surface of the particles and in the far field. A new test is introduced to check that the surface fields fulfill Maxwells equations allowing evaluation of the validity of the internal field. Calculations of the scattering cross section show a faster rate of convergence for the principal mode theory. We show that for metallic particles the internal field is the most significant source of error.

Design, synthesis and structure–activity relationships of (indo-3-yl) heterocyclic derivatives as agonists of the CB1 receptor. Discovery of a clinical candidate

We report an expansion of the structure-activity relationship (SAR) of a novel series of indole-3-heterocyclic CB1 receptor agonists. Starting from the potent but poorly soluble lead, 1, a rational approach was taken in order to balance solubility, hERG activity and potency while retaining the desired long duration of action within the mouse tail flick test. This led to the discovery of compound 38 which successfully progressed into clinical development.

Discovery of potent and orally bioavailable heterocycle-based cannabinoid CB1 receptor agonists

Novel 3-(1H-indol-3-yl)-1,2,4-oxadiazoles and -thiadiazoles were synthesized and found to be potent CB1 cannabinoid receptor agonists. The oral bioavailability of these compounds could be dramatically improved by optimization studies of the side chains attached to the indole and oxadiazole cores, leading to identification of a CB1 receptor agonist with good oral activity in a range of preclinical models of antinociception and antihyperalgesia.

Enhancing ultraviolet spontaneous emission with a designed quantum vacuum

We determine how to alter the properties of the quantum vacuum at ultraviolet wavelengths to simultaneously enhance the spontaneous transition rates and the far field detection rate of quantum emitters. We find the response of several complex nanostructures in the 200 - 400 nm range, where many organic molecules have fluorescent responses, using an analytic decomposition of the electromagnetic response in terms of continuous spectra of plane waves and discrete sets of modes. Coupling a nanorod with an aluminum substrate gives decay rates up to 2.7 × 103 times larger than the decay rate in vacuum and enhancements of 824 for the far field emission into the entire upper semi-space and of 2.04 × 103 for emission within a cone with a 60° semi-angle. This effect is due to both an enhancement of the field at the emitters position and a reshaping of the radiation patterns near mode resonances and cannot be obtained by replacing the aluminum substrate with a second nanoparticle or with a fused silica substrate. These large decay rates and far field enhancement factors will be very useful in the detection of fluorescence signals, as these resonances can be shifted by changing the dimensions of the nanorod. Moreover, these nanostructures have potential for nano-lasing because the Q factors of these resonances can reach 107.9, higher than the Q factors observed in nano-lasers.