Fourteen commercial polyols have been characterized by GPC, NMR spectroscopy, and elemental analysis. From these, eight corresponding tosylates, six nitrate esters, seven mesylates, 13 alkynes, and 14 azides have been prepared and all these derivatives have been fully characterized. Five alkyne monomers and eight azide monomers were also prepared. Twelve alkynes and 13 azides (functionality 2–4) were combined in 1,3‐dipolar cycloaddition reactions under neat conditions to prepare triazole‐cured polymers, avoiding any heavy metal catalyst. Characterization by NMR spectroscopy, elemental analysis, and gel permeation chromatography indicated triazole polymers 14, 22, 23, 28, and 30 with degrees of polymerization of 17–28 to be the best candidates for future work. © 2007 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 238–256, 2008

α-Conotoxins are peptide neurotoxins that selectively inhibit various subtypes of nicotinic acetylcholine receptors. They are important research tools for studying numerous pharmacological disorders, with profound potential for developing drug leads for treating pain, tobacco addiction, and other conditions. They are characterized by the presence of two disulfide bonds connected in a globular arrangement, which stabilizes a bioactive helical conformation. Despite extensive structure-activity relationship studies that have produced α-conotoxin analogs with increased potency and selectivity towards specific nicotinic acetylcholine receptor subtypes, the efficient production of diversity-oriented α-conotoxin combinatorial libraries has been limited by inefficient folding and purification procedures. We have investigated the optimized conditions for the reliable folding of α-conotoxins using simplified oxidation procedures for use in the accelerated production of synthetic combinatorial libraries of α-conotoxins. To this end, the effect of co-solvent, redox reagents, pH, and temperature on the proportion of disulfide bond isomers was determined for α-conotoxins exhibiting commonly known Cys loop spacing frameworks. In addition, we have developed high-throughput 'semi-purification' methods for the quick and efficient parallel preparation of α-conotoxin libraries for use in accelerated structure-activity relationship studies. Our simplified procedures represent an effective strategy for the preparation of large arrays of correctly folded α-conotoxin analogs and permit the rapid identification of active hits directly from high-throughput pharmacological screening assays.

α-Conotoxins are disulfide-rich peptide neurotoxins that selectively inhibit neuronal nicotinic acetylcholine receptors (nAChRs). The α3β4 nAChR subtype has been identified as a novel target for managing nicotine addiction. Using a mixture-based positional-scanning synthetic combinatorial library (PS-SCL) with the α4/4-conotoxin BuIA framework, we discovered a highly potent and selective α3β4 nAChR antagonist. The initial PS-SCL consisted of a total of 113 379 904 sequences that were screened for α3β4 nAChR inhibition, which facilitated the design and synthesis of a second generation library of 64 individual α-conotoxin derivatives. Eleven analogues were identified as α3β4 nAChR antagonists, with TP-2212-59 exhibiting the most potent antagonistic activity and selectivity over the α3β2 and α4β2 nAChR subtypes. Final electrophysiological characterization demonstrated that TP-2212-59 inhibited acetylcholine evoked currents in α3β4 nAChRs heterogeneously expressed in Xenopus laevis oocytes with a calculated IC50 of 2.3 nM and exhibited more than 1000-fold selectivity over the α3β2 and α7 nAChR subtypes. As such, TP-2212-59 is among the most potent α3β4 nAChRs antagonists identified to date and further demonstrates the utility of mixture-based combinatorial libraries in the discovery of novel α-conotoxin derivatives with refined pharmacological activity.

The α4β2 nicotinic acetylcholine receptor (nAChR) is an important target for currently approved smoking cessation therapeutics. However, the development of highly selective α4β2 nAChR antagonists remains a significant challenge. α-Conotoxin GID is an antagonist of α4β2 nAChRs, though it is significantly more potent toward the α3β2 and α7 subtypes. With the goal of obtaining further insights into α-conotoxin GID/nAChR interactions that could lead to the design of GID analogues with improved affinity for α4β2 nAChRs, we built a homology model of the GID/α4β2 complex using an X-ray co-crystal structure of an α-conotoxin/acetylcholine binding protein (AChBP) complex. Several additional interactions that could potentially enhance the affinity of GID for α4β2 nAChRs were observed in our model, which led to the design and synthesis of 22 GID analogues. Seven analogues displayed inhibitory activity toward α4β2 nAChRs that was comparable to GID. Significantly, both GID[A10S] and GID[V13I] demonstrated moderately improved selectivity toward α4β2 over α3β2 when compared with GID, while GID[V18N] exhibited no measurable inhibitory activity for the α3β2 subtype, yet retained inhibitory activity for α4β2. In this regard, GID[V18N] is the most α4β2 nAChR selective α-conotoxin analogue identified to date.

Marine cone snail venoms consist of large, naturally occurring combinatorial libraries of disulfide-constrained peptide neurotoxins known as conotoxins, which have profound potential in the development of analgesics. In this study, we report a synthetic combinatorial strategy that probes the hypervariable regions of conotoxin frameworks to discover novel analgesic agents by utilizing high diversity mixture-based positional-scanning synthetic combinatorial libraries (PS-SCLs). We hypothesized that the direct in vivo testing of these mixture-based combinatorial library samples during the discovery phase would facilitate the identification of novel individual compounds with desirable antinociceptive profiles while simultaneously eliminating many compounds with poor activity or liabilities of locomotion and respiration. A PS-SCL was designed based on the α-conotoxin RgIA-ΔR n-loop region and consisted of 10,648 compounds systematically arranged into 66 mixture samples. Mixtures were directly screened in vivo using the mouse 55 °C warm-water tail-withdrawal assay, which allowed deconvolution of amino acid residues at each position that confer antinociceptive activity. A second generation library of 36 individual α-conotoxin analogues was synthesized using systematic combinations of amino acids identified from PS-SCL deconvolution and further screened for antinociceptive activity. Six individual analogues exhibited comparable antinociceptive activity to that of the recognized analgesic α-conotoxin RgIA-ΔR, and were selected for further examination of antinociceptive, respiratory, and locomotor effects. Three lead compounds were identified that produced dose-dependent antinociception without significant respiratory depression or decreased locomotor activity. Our results represent a unique approach for rapidly developing novel lead α-conotoxin analogues as low-liability analgesics with promising therapeutic potential.

Thirteen triazole polymers were prepared as potential rocket propellant binders by the reactions of various diacetylenes and diazides. The reaction of E300 dipropiolate (1) with diazide (2) obtained from tetraethylene glycol was selected to study the effects of concentration of the tetraacetylene functionalized crosslinker (3) on the mechanical properties of resulting triazole polymers. The modulus of the polymers increased, whereas the strain (% elongation at failure) decreased with increasing percentage of crosslinker. The resulting triazole polymers also showed that the desired mechanical properties could be obtained by adjusting the crosslinker concentration during the polymerization. Addition of 43 wt % aluminum filler did not significantly affect the strain. The modulus of these triazole polymers was comparable with typical polyurethane elastomeric matrices for rocket propellants.

The effect of filler loading on the mechanical properties of crosslinked triazole polymers obtained by polymerization of E300 dipropiolate (1) with diazide (2) obtained from tetraethylene glycol using tetraacetylene functionalized crosslinker (3) was studied systematically. Aluminum (10-14 lm) was used as the primary filler during the formulations; the effect of secondary fillers such as aluminum (<75 lm), NaCl (45-50 and 83-105 lm) was studied with the increase in the total filler loading. The modulus of the aluminum-filled crosslinked triazole polymers increases with the increase in the filler content while using either particle sized aluminum powder. The use of Al (particle size <75 lm) and NaCl (particle size 45-50 lm and 83-105 lm) as secondary or additional fillers while using aluminum (10-14 lm) as the main filler, has a diminishing effect on the modulus and strain of the crosslinked triazole polymers. Triazole polymers described herein have the ability to wet and adhere to large quantities of these inorganic salts and thus maintain mechanical properties of the composite comparable to typical polyurethane elastomeric matrices, regardless of the chemistry of the particulate filler, which imparts an important and necessary binder characteristic for energetic composites.

ABSTRACT:The mechanical properties of crosslinked polymers depend on their structural features, one of which is the functionality of the crosslinks in a polymer network. To study the effect of crosslink functionality (U) on the mechanical properties of 1,2,3-triazole polymers for potential application as rocket propellant binders, crosslinkers with different U's (3, 4, 6, 16, 32, and 64) were used in the polymerization. As the percentage of acetylenic groups provided by crosslinker was kept constant and the functionality of the crosslinker increased, the resulting polymer showed a higher modulus but a lower strain. Compared to traditional polyurethane binders, 1,2,3-triazole polymers showed comparable mechanical properties, although the stress and modulus tended to be lower and the strain capability tended to be greater for the triazole-linked rubbers.