N-(Anilinoethyl)amide Melatonergic Ligands with Improved Water Solubility and Metabolic Stability

The MT₂-selective melatonin receptor ligand UCM765 (N-(2-((3-methoxyphenyl)(phenyl)amino)ethyl)acetamide), showed interesting sleep inducing, analgesic and anxiolytic properties in rodents, but suffers from low water solubility and modest metabolic stability. To overcome these limitations, different strategies were investigated, including modification of metabolically liable sites, introduction of hydrophilic substituents and design of more basic derivatives. Thermodynamic solubility, microsomal stability and lipophilicity of new compounds were experimentally evaluated, together with their MT₁ and MT₂ binding affinities. Introduction of a m-hydroxymethyl substituent on the phenyl ring of UCM765 and replacement of the replacement of the N,N-diphenyl-amino scaffold with a N-methyl-N-phenyl-amino one led to highly soluble compounds with good microsomal stability and receptor binding affinity. Docking studies into the receptor crystal structure provided a rationale for their binding affinity. Pharmacokinetic characterization in rats highlighted higher plasma concentrations for the N-methyl-N-phenyl-amino derivative, consistent with its improved microsomal stability and makes this compound worthy of consideration for further pharmacological investigation.     

Potent,Metabolically Stable 2‐Alkyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐adenines as Adenosine A2A Receptor Ligands

Inhibition of adenosine A_2A receptors has been shown to elicit a therapeutic response in preclinical animal models of Parkinson’s disease (PD). We previously identified the triazolo‐9H‐purine, ST1535, as a potent A_2AR antagonist. Studies revealed that ST1535 is extensively hydroxylated at the ω‐1 position of the butyl side chain. Here, we describe the synthesis and evaluation of derivatives in which the ω‐1 position has been substituted (F, Me, OH) in order to block metabolism. The stability of the compounds was evaluated in human liver microsomes (HLM), and the affinity for A_2AR was determined. Two compounds, (2‐(3,3‐dimethylbutyl)‐9‐methyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐purin‐6‐amine ( 3 b ) and 4‐(6‐amino‐9‐methyl‐8‐(2H‐1,2,3‐triazol‐2‐yl)‐9H‐purin‐2‐yl)‐2‐methylbutan‐2‐ol ( 3 c ), exhibited good affinity against A_2AR (K_i=0.4 nM and 2 nM , respectively) and high in vitro metabolic stability (89.5 % and 95.3 % recovery, respectively, after incubation with HLM for two hours).     

A Silicon Modulator Enabling RF Over Fiber for 802.11 OFDM Signals

We investigate the linearity properties of silicon modulators and show that, contrary to the traditional lithium niobate Mach–Zehnder modulators (MZMs), the third-order intermodulation distortion (IMD3) for silicon modulators is a function of the modulator bias point. The bias point for silicon modulators can be chosen to reduce the IMD3 well below that of standard lithium niobate MZMs. Given the cost and integration advantages of the silicon photonics technology, silicon modulators offer significant advantages for emerging radio over fiber applications. As an example, we examine, for the first time to our knowledge, a silicon modulator for converting analog 802.11 RF signals to the optical domain, achieving an error vector magnitude of −30 dB.      

DQPSK: When Is a Narrow Filter Receiver Good Enough?

In this paper, we investigate experimentally and via simulation the pros and cons of a narrow filter receiver for differential quadrature phase-shift keying based on a single optical filter and eschewing the conventional asymmetrical Mach-Zehnder interferometer structure. We quantify the performance differences between the two receivers, allowing system designers and operators to determine when the less complex narrow filter receiver might be the appropriate choice. We numerically optimize the 3-dB bandwidth and center frequency of the narrow filter and show it is more robust to carrier frequency detuning than the conventional solution. We show that the narrow filter receiver is more tolerant to chromatic dispersion (CD) than the conventional one, and equally tolerant to first-order polarization-mode dispersion. We show the impact of the 3-dB bandwidth on the receiver performance when CD accumulates. Finally, we show via experiments and simulations that the 3 dB advantage of the conventional receiver vanishes when the nonlinear impairments are fiber nonlinearities; comparing the two receivers at the optimum launch power for a 25 times 80 km system, the difference in optical SNR margin is reduced to ~1.6 dB. Experiments are conducted at 42 Gb/s using a commercially available narrow filter for reception.     

A Second Generation of Carbamate‐Based Fatty Acid Amide Hydrolase Inhibitors with Improved Activity in vivo

The fatty acid ethanolamides are a class of signaling lipids that include agonists at cannabinoid and α type peroxisome proliferator‐activated receptors (PPARα). In the brain, these compounds are primarily hydrolyzed by the intracellular serine enzyme fatty acid amide hydrolase (FAAH). O‐aryl carbamate FAAH inhibitors such as URB597 are being evaluated clinically for the treatment of pain and anxiety, but interactions with carboxylesterases in liver might limit their usefulness. Here we explore two strategies aimed at overcoming this limitation. Lipophilic N‐terminal substitutions, which enhance FAAH recognition, yield potent inhibitors but render such compounds susceptible to attack by broad‐spectrum hydrolases and inactive in vivo. By contrast, polar electron‐donating O‐aryl substituents, which decrease carbamate reactivity, yield compounds, such as URB694, that are highly potent FAAH inhibitors in vivo and less reactive with off‐target carboxylesterases. The results suggest that an approach balancing inhibitor reactivity with target recognition produces FAAH inhibitors that display significantly improved drug‐likeness.     

N‐(Anilinoethyl)amides: Design and Synthesis of Metabolically Stable,Selective Melatonin Receptor Ligands

The class of N‐(anilinoethyl)amides includes melatonin receptor ligands with varied subtype selectivity and intrinsic activity. One of these ligands, the MT₂‐selective partial agonist UCM765 (N‐{2‐[(3‐methoxyphenyl)phenylamino]ethyl}acetamide), had evidenced hypnotic effects in rodents at doses ≥40 mg kg^?1 (s.c.), in spite of its sub‐nanomolar affinity for human melatonin receptors. Supposing that its low in vivo potency could be due, at least in part, to metabolic liability in rat liver, UCM765 was incubated with rat liver S9 fraction and rat, mouse, or human microsomes, and the major metabolites were identified by LC–MS, synthesized, and in vitro tested for their affinity toward MT₁ and MT₂ receptors. The obtained information was exploited to design novel analogues of UCM765 that are more resistant to in vitro oxidative degradation, while maintaining a similar binding profile. The analogue UCM924 (N‐{2‐[(3‐bromophenyl)‐(4‐fluorophenyl)amino]ethyl}acetamide) displayed a binding profile similar to that of UCM765 on cloned human receptors (MT₂‐selective partial agonist) and a significantly longer half‐life in the presence of rat liver S9 fraction.     

Structure–Property Relationships of a Class of Carbamate‐Based Fatty Acid Amide Hydrolase (FAAH) Inhibitors: Chemical and Biological Stability

Cyclohexylcarbamic acid aryl esters are a class of fatty acid amide hydrolase (FAAH) inhibitors, which includes the reference compound URB597. The reactivity of their carbamate fragment is involved in pharmacological activity and may affect their pharmacokinetic and toxicological properties. We conducted in vitro stability experiments in chemical and biological environments to investigate the structure–stability relationships in this class of compounds. The results show that electrophilicity of the carbamate influences chemical stability, as suggested by the relation between the rate constant of alkaline hydrolysis (log k_pH9) and the energy of the lowest unoccupied molecular orbital (LUMO). Introduction of small electron‐donor substituents at conjugated positions of the O‐aryl moiety increased the overall hydrolytic stability of the carbamate group without affecting FAAH inhibitory potency, whereas peripheral non‐conjugated hydrophilic groups, which favor FAAH recognition, helped decrease oxidative metabolism in the liver.     

Low-Complexity Compensation of SOA Nonlinearity for Single-Channel PSK and OOK

Carrier density fluctuations in semiconductor optical amplifiers (SOAs) impose penalties on phase-shift keying (PSK) signals due to nonlinear phase noise (NLPN), and on-off keying (OOK) signals due to self-gain modulation. In this paper, we propose a simple scheme to equalize the impairments induced by SOA nonlinearities, derived from the small signal analysis of carrier density fluctuations. We demonstrate via simulation almost complete cancelation of the NLPN added by a saturated SOA on a differential PSK signal. We demonstrate via both simulations and experiment the effectiveness of the method for mitigation of nonlinear distortions imposed by SOAs on an OOK signal.      

High-Bit-Rate Dense SS-WDM PON Using SOA-Based Noise Reduction With a Novel Balanced Detection

The major drawback of incoherent broadband sources (BBSs) is their inherent intensity noise. Semiconductor optical amplifiers (SOAs) can be exploited at the transmitter to mitigate this noise. Optical filtering at the receiver, however, leads to the return of most of suppressed noise. Wider filtering at the receiver is the best known strategy to maintain performance gains, at the price of reduced spectral efficiency due to the tradeoff between noise cleaning and adjacent channel crosstalk. We introduce a novel balanced receiver for wavelength division multiplexing (WDM) systems that maintains greater noise cleaning and leaves spectral efficiency unchanged. Unlike standard receivers, our balanced scheme does not filter the desired signal. In this paper, we first demonstrate that the newly proposed receiver is equivalent to standard WDM receivers when no SOA for noise cleaning is present at the transmitter. Although a 2.9-dB power penalty is incurred, network capacity is unchanged, i.e., bit error rate (BER) floors due to intensity noise are the same. When SOAs are employed to mitigate severe intensity noise, we show that our receiver outperforms the wide filtering strategy by two orders of magnitude. Dense WDM capacity is demonstrated up to 10 Gb/s using a thermal source, a saturated SOA, and the balanced detection scheme. A BER of 10^-6 is achieved at 10 Gb/s; further improvement is possible using low overhead forward error correction or a better SOA design. This demonstrates the ability of spectrum-sliced wavelength division multiplexing (SS-WDM) passive optical networks (PONs) to operate at 10 Gb/s at good spectral efficiency. Error performance better than 10^-9 is achieved up to 8 Gb/s with 30-GHz optical channel bandwidth and 100-GHz spacing.