Hyperthermia induced by transient receptor potential vanilloid-1 (TRPV1) antagonists in human clinical trials: Insights from mathematical modeling and meta-analysis.

Antagonists of the transient receptor potential vanilloid-1 (TRPV1) channel alter body temperature (T) in laboratory animals and humans: most cause hyperthermia; some produce hypothermia; and yet others have no effect. TRPV1 can be activated by capsaicin (CAP), protons (low pH), and heat. First-generation (polymodal) TRPV1 antagonists potently block all three TRPV1 activation modes.

Dibenzazepines and dibenzoxazepines as sodium channel blockers.

We have identified two related series of dibenzazepine and dibenzoxazepine sodium channel blockers, which showed good potency on Nav1.7 in FLIPR-based and electrophysiological functional assays.

N-Aryl azacycles as novel sodium channel blockers.

We have identified a new series of N-aryl azacycles as sodium channel blockers, which showed good potency on Nav1.7 in FLIPR-based and electrophysiological functional assays. Analogs from this series possessed selectivity over hERG, reasonable oral exposure in rat PK studies and are predicted to have limited CNS penetration.

Structure-activity relationship studies and discovery of a potent transient receptor potential vanilloid (TRPV1) antagonist 4-[3-chloro-5-[(1S)-1,2-dihydroxyethyl]-2-pyridyl]-N-[5-(trifluoromethyl)-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxamide (V116517) as a clinical candidate for pain management.

A series of novel tetrahydropyridinecarboxamide TRPV1 antagonists were prepared and evaluated in an effort to optimize properties of previously described lead compounds from piperazinecarboxamide series. The compounds were evaluated for their ability to block capsaicin and acid-induced calcium influx in CHO cells expressing human TRPV1. The most potent of these TRPV1 antagonists were further characterized in pharmacokinetic, efficacy, and body temperature studies.

Studies examining the relationship between the chemical structure of protoxin II and its activity on voltage gated sodium channels.

The aqueous solution structure of protoxin II (ProTx II) indicated that the toxin comprises a well-defined inhibitor cystine knot (ICK) backbone region and a flexible C-terminal tail region, similar to previously described NaSpTx III tarantula toxins. In the present study we sought to explore the structure-activity relationship of the two regions of the ProTx II molecule. As a first step, chimeric toxins of ProTx II and PaTx I were synthesized and their biological activities on Nav1.

Roles of μ-opioid receptors and nociceptin/orphanin FQ peptide receptors in buprenorphine-induced physiological responses in primates.

Buprenorphine is known as a μ-opioid peptide (MOP) receptor agonist, but its antinociception is compromised by the activation of nociceptin/orphanin FQ peptide (NOP) receptors in rodents. The aim of this study was to investigate the roles of MOP and NOP receptors in regulating buprenorphine-induced physiological responses in primates (rhesus monkeys). The effects of MOP antagonist (naltrexone), NOP antagonist [(±)-1-[(3R*,4R*)-1-(cyclooctylmethyl)-3-(hydroxymethyl)-4-piperidinyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397)], and NOP agonists [(1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.

Cysteine racemization during the Fmoc solid phase peptide synthesis of the Nav1.7-selective peptide--protoxin II.

Protoxin II is biologically active peptide containing the inhibitory cystine knot motif. A synthetic version of the toxin was generated with standard Fmoc solid phase peptide synthesis. If N-methylmorpholine was used as a base during synthesis of the linear protoxin II, it was found that a significant amount of racemization (approximately 50%) was observed during the process of cysteine residue coupling.

Display of somatostatin-related peptides in the complementarity determining regions of an antibody light chain.

Peptide display in antibody complementarity determining regions (CDRs) offers several advantages over other peptide display systems including the potential to graft heterologous peptide sequences into multiple positions in the same backbone molecule. Despite the presence of six CDRs in an antibody variable domain, the majority of insertions reported have been made in heavy chain CDR3 (h-CDR3) which may be explained in part by the highly variable length and sequence diversity found in h-CDR3 in native antibodies. The ability to graft peptide sequences into CDRs is restricted by amino acids in these loops that make structural contacts to framework regions or are oriented towards the hydrophobic interior and are important for the proper folding of the antibody.

8-Substituted analogues of 3-(3-cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-adenine: highly potent and selective PDE4 inhibitors.

3-(3-Cyclopentyloxy-4-methoxy-benzyl)-8-isopropyl-adenine V11294 (1) has been identified as a lead structure, which selectively inhibits human lung PDE4 (436 nM) and is also active in a number of in vitro and in vivo models of inflammation. Here we describe the synthesis and pharmacology of a series of highly potent 8-[(benzyloxy)methyl]-substituted analogues, with potencies in the range 10-300 nM. In addition, several compounds showed interesting PDE4 subtype specificities, for example, the 3-thienyl derivative 5v, which showed 6-10 nM potency at PDE4B, D3, and D5 and a 20- to 200-fold selectivity over A and D2, respectively.

Synthesis and evaluation of pyridazinylpiperazines as vanilloid receptor 1 antagonists.

A structurally biased chemical library of pyridazinylpiperazine analogs was prepared in an effort to improve the pharmaceutical and pharmacological profile of the lead compound N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide (BCTC). The library was evaluated for VR1 antagonist activity in capsaicin-induced (CAP) and pH5.5-induced (pH) FLIPR assays in a human VR1-expressing HEK293 cell line.

Design and synthesis of 4-phenyl piperidine compounds targeting the mu receptor.

Small molecule mu agonists based on the 4-phenyl piperidine scaffold were designed and synthesized to further investigate the therapeutic potential of loperamide analogs. The resulting compounds show excellent agonistic activity towards the human mu receptor with interesting SAR trends within the series.

1,3-Dihydro-2,1,3-benzothiadiazol-2,2-diones and 3,4-dihydro-1H-2,1,3-benzothidiazin-2,2-diones as ligands for the NOP receptor.

A series of 1,3-dihydro-2,1,3-benzothiadiazol-2,2-diones (I) and 3,4-dihydro-1H-2,1,3-benzothidiazin-2,2-diones (II) were prepared. While the five-member ring series (I) did not show good affinity for opioid receptors, the six-member ring series (II) exhibited extremely high affinity and selectivity for the NOP receptor and showed full agonist activity, as determined by stimulation of GTPgamma[35S] binding.

DiPOA ([8-(3,3-diphenyl-propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-yl]-acetic acid), a novel, systemically available, and peripherally restricted mu opioid agonist with antihyperalgesic activity: I. In vitro pharmacological characterization and pharmacokinetic properties.

Mu opioid receptors are present throughout the central and peripheral nervous systems. Peripheral inflammation causes an increase in mu receptor levels on peripheral terminals of primary afferent neurons. Recent studies indicate that activation of peripheral mu receptors produces antihyperalgesic effects in animals and humans.

An efficient parallel synthesis of capsazepine and capsazepine analogs.

Capsazepine (CPZ, 1) is a well-known vanilloid receptor (VR1) antagonist that has been cited widely used in the literature. However the current synthetic methods used for the total synthesis of CPZ are lengthy, involve multiple purification steps, and produce low yields. Here we describe a new and highly efficient synthesis of benzazepine 3, a synthetic precursor of CPZ, in only two steps and 59% overall yield from a commercially available tetralone 2 via a Schmidt reaction as a key step.

Design and synthesis of novel small molecule N/OFQ receptor antagonists.

Small molecule N/OFQ receptor antagonists were designed and synthesized to further investigate the therapeutic potential of N/OFQ receptor modulators. The resulting octahydrobenzimidazol-2-ones 14 and 23 show excellent antagonistic activity towards both N/OFQ and mu receptors with high affinity to the human N/OFQ receptor.

4-(2-pyridyl)piperazine-1-carboxamides: potent vanilloid receptor 1 antagonists.

A series of 4-(2-pyridyl)piperazine-1-carboxamide analogues based on the lead compound 1 was synthesized and evaluated for VR1 antagonist activity in capsaicin-induced (CAP) and pH (5.5)-induced (pH) FLIPR assays in a rat VR1-expressing HEK293 cell line. Potent VR1 antagonists were identified through SAR studies.

Parallel synthesis of a biased library of thiazolidinones as novel sodium channel antagonists.

A biased chemical library containing 91 differentially substituted thiazolidinones was prepared in an effort to improve the pharmacology of a known anticonvulsant agent V102862. The collection was prepared in a single step multi-component condensation reaction that produced good yields and very high crude purity (75%-85%). Seven compounds, identified within the library were shown to be more potent than V102862, our parent reference compound, in an electrophysiological assay measuring sodium channel antagonism.

Pharmacology of a new cyclic nucleotide phosphodiesterase type 4 inhibitor, V11294.

V11294 is a new cyclic nucleotide phosphodiesterase type 4 (PDE4) inhibitor of the rolipram class. In this report we present the pharmacological profile of V11294. V11294 inhibited PDE4 isolated from human lung with IC(50) 405 nM, compared to 3700 nM for rolipram.

Human B1 and B2 bradykinin receptors and their agonists target caveolae-related lipid rafts to different degrees in HEK293 cells.

To address the targeting of G protein-coupled receptors to caveolae-related lipid rafts (CLR), we studied the human B2 (B2R) and B1 (B1R) bradykinin receptor subtypes in HEK293 cells. CLR were enriched on the basis of their unique buoyant density and composition of cholesterol, caveolin-1, and flotillin-1 but not clathrin. CLR contained B2R and B1R as determined by both receptor immunoblotting and the increase in specific activity of receptor agonist binding to cells at both 4 and 37 degrees C when binding was followed by CLR enrichment.

Novel, potent ORL-1 receptor agonist peptides containing alpha-Helix-promoting conformational constraints.

The ORL-1 receptor has recently been cloned and is implicated in a wide variety of physiological and pathophysiological processes. Toward the goal of elucidating important features of the receptor-bound conformation of the endogenous ligand, nociceptin (NC), several conformationally constrained analogues were prepared. Either alpha-aminoisobutyric acid (Aib) or N-methylalanine (MeAla) were inserted as replacement(s) for Ala7, Ala11, or Ala15 in the native NC sequence (FGGFTGARKSARKLANQ).

Solid-phase and solution-phase parallel synthesis of tetrahydro-isoquinolines via Pictet-Spengler reaction.

An efficient parallel synthesis of 6,7-dimethoxytetrahydroisoquinolines is reported. The key reaction step is 3,4-dimethoxyphenethylimines reacting with acid chlorides to form an N-acyliminium ion intermediate, which undergoes Pictet-Spengler condensation to give the desired products in >80% yield. Both solution-phase and solid-phase synthesis of 6,7-dimethoxytetrahydroisoquinolines are described.