Purpose
This two-part review summarizes the current knowledge of physiological mechanisms, pharmacological modalities and controversial issues surrounding preemptive analgesia.

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Preemptive analgesia I: physiological pathways and pharmacological modalities.

The vanilloid receptor-1 (TRPV1 or VR1) is a member of the transient receptor potential (TRP) family of ion channels and plays a role in regulating the function of sensory nerves. A growing body of evidence demonstrates the therapeutic potential of TRPV1 modulators, particularly in the management of pain. As a result of our screening efforts, we identified (E)-3-(4-tert-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide (1), an antagonist that blocks the capsaicin-induced and pH-induced uptake of (45)Ca(2+) in TRPV1-expressing Chinese hamster ovary cells with IC(50) values of 17 +/- 5 and 150 +/- 80 nM, respectively. In this report, we describe the synthesis and structure-activity relationship of a series of N-aryl cinnamides, the most potent of which (49a and 49b) exhibit good oral bioavailability in rats (F(oral) = 39% and 17%, respectively).

Discovery of Potent, Orally Available Vanilloid Receptor-1 Antagonists. Structure−Activity Relationship of N-Aryl Cinnamides

The identification and cloning of the vanilloid receptor 1 (TRPV1) represented a significant step for the understanding of the molecular mechanisms underlying the transduction of noxious chemical and thermal stimuli by peripheral nociceptors. TRPV1 is a non-selective cation channel gated by noxious heat, vanilloids and extracellular protons. TRPV1 channel activity is remarkably potentiated by pro-inflammatory agents, a phenomenon that is thought to underlie the peripheral sensitisation of nociceptors that leads to thermal hyperalgesia. Cumulative evidence is building a strong case for the involvement of this receptor in the etiology of both peripheral and visceral inflammatory pain, such as inflammatory bowel disease, bladder inflammation and cancer pain. The validation of TRPV1 receptor as a key therapeutic target for pain management has thrust intensive drug discovery programs aimed at developing orally active antagonists of the receptor protein. Nonetheless, the real challenge of these drug discovery platforms is to develop antagonists that preserve the physiological activity of TRPV1 receptors while correcting over-active channels. This is a condition to ensure normal pro-prioceptive and nociceptive responses that represent a safety mechanism to prevent tissue injury. Recent and exciting advances in the function, dysfunction and modulation of this receptor will be the focus of this review.

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Physiology and pharmacology of the vanilloid receptor

The present invention comprises a new class of compounds useful for the prophylaxisand treatment of protein kinase mediated diseases, including inflammation,cancer and related conditions. The compounds have a general Formula I, whereinA1, A2, A3, B, R1, R2, R3 and R4 are defined herein. Accordingly, the inventionalso comprises pharmaceutical compositions comprising the compounds of theinvention, methods for the prophylaxis and treatment of kinase mediated diseasesusing the compounds and compositions of the invention, and intermediates andprocesses useful for the preparation of compounds of the invention.

Aryl nitrogen-containing bicyclic compounds and their use as kinase inhibitors

α- and β-amino acid hydroxyethylamino sulfonamide compounds are effective as retroviral protease inhibitors, and in particular as inhibitors of HIV protease.

α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors

The invention relates to sulfonyl amine derivatives of formula IA 
wherein R 5A , X 1 , X 2 , R 9 and R 10 are as defined herein, which derivatives are useful as bradykinin B 1 receptor antagonists.

Bradykinin receptor antagonists

The present invention relates to quinazolinones of formula (I) wherein R1 is hal; a); b); or c); X is N or CR8; R2 is hal; nitro; C1-C6alkylcarbonyl; C1-C6alkyl or C3-C6cycloalkyl; R3 is C1-C6alkyl; C1-C6alkoxy or amino; and wherein the further radicals have the meanings as defined in the specification, which compounds exhibit human vanilloid antagonistic activity; to processes for their production, their use as pharmaceuticals and to pharmaceutical compositions comprising them.

Quinazolinone derivatives useful as anti-hyperalgesic agents

The present invention relates to the use of a chromone compound of the formula (I) wherein R1, R2, R3, R4, R5 and m are as defined in the specification and in the claims, in free form or in salt form, and, where possible, in acid addition salt form, as a vanilloid antagonist.

Chromone Derivatives Useful as Vanilloid Antagonists

The present invention relates to the use of a quinazolinone compound of the formula (I) wherein R1, R2, R3, R4, R5 and m are as defined in the specification and in the claims, in free form or in salt form, and, where possible, in acid addition salt form, as a vanilloid.

Quinazolinone derivatives useful as vanilloid antagonists

The present invention relates to quinazolinone compounds of the formula wherein R2, R3, R5, R6 R7 and R8 are as defined in the specification and in the claims, in free form or in salt form, processes for their preparation and their use as pharmaceuticals, particularly in the treatment of disorders ameliorated by administration of TRPV1 antagonists.

Dziadulewicz Edward Karol

Papers

Bradykinin receptor antagonists

Quinazolinone derivatives useful as anti-hyperalgesic agents

Chromone Derivatives Useful as Vanilloid Antagonists

Quinazolinone derivatives useful as vanilloid antagonists

Trisubstituted quinazolinone derivatives as vanilloid antagonists