Estimation of the lipophilicity of purine-2,6-dione-based TRPA1 antagonists and PDE4/7 inhibitors with analgesic activity (original) (raw)

The case for the development of novel analgesic agents targeting both fatty acid amide hydrolase and either cyclooxygenase or TRPV1

British journal of pharmacology, 2009

Although the dominant approach to drug development is the design of compounds selective for a given target, compounds targeting more than one biological process may have superior efficacy, or alternatively a better safety profile than standard selective compounds. Here, this possibility has been explored with respect to the endocannabinoid system and pain. Compounds inhibiting the enzyme fatty acid amide hydrolase (FAAH), by increasing local endocannabinoid tone, produce potentially useful effects in models of inflammatory and possibly neuropathic pain. Local increases in levels of the endocannabinoid anandamide potentiate the actions of cyclooxygenase inhibitors, raising the possibility that compounds inhibiting both FAAH and cyclooxygenase can be as effective as non-steroidal anti-inflammatory drugs but with a reduced cyclooxygenase inhibitory 'load'. An ibuprofen analogue active in models of visceral pain and with FAAH and cyclooxygenase inhibitory properties has been identified. Another approach, built in to the experimental analgesic compound N-arachidonoylserotonin, is the combination of FAAH inhibitory and transient receptor potential vanilloid type 1 antagonist properties. Although finding the right balance of actions upon the two targets is a key to success, it is hoped that dual-action compounds of the types illustrated in this review will prove to be useful analgesic drugs.

Analgesic and anti-inflammatory activity of 7-substituted purine-2,6-diones

Pharmacological Reports, 2014

Background: In an effort to develop new analgesic and anti-inflammatory agents, we determined a series of 7-substituted purine-2,6-diones. Methods: The obtained compounds (1-6) were evaluated pharmacologically in four in vivo models: the writhing syndrome, the formalin tests, the carrageenan-induced edema model and the zymosaninduced peritonitis. The influence of the investigated compounds on the phosphodiesterase (PDE) and PDE4B activity was also determined. In addition, determination of the antioxidant activity was determined by the FRAP assay. Results: A majority of the tested compounds showed a significant analgesic and anti-inflammatory activity. The strongest analgesic and anti-inflammatory effect was observed for 1 and 2. The active compound 1 was more efficient than theophylline in inhibiting the PDE and more efficient than rolipram in inhibiting the PDE4B activity. The tested compounds did not show significant antioxidant properties. Conclusion: Active compounds (1-6) inhibited the PDE activity, while compound 1 significantly inhibited the PDE4B activity, what may suggest that this mechanism may be involved in their analgesic/ anti-inflammatory properties.

TRPA1 involvement in analgesia induced by Tabernaemontana catharinensis ethyl acetate fraction in mice

Phytomedicine, 2019

Background: Ionic channels such as the transient receptor potential ankyrin 1 (TRPA1) are essential for the detection and transmission of painful stimuli. In this sense, new TRPA1 antagonists have been searched as analgesics. Purpose: Preclinical studies support the antinociceptive activity of Tabernaemontana catharinensis ethyl acetate fraction (Eta), which has constituents previously identified as TRPA1 antagonists (gallic acid). It was verified for the first time the involvement of the TRPA1 on Eta's antinociceptive and anti-inflammatory effects in mice pain models. Study design: It was evaluated the Eta's effect (0.01-100 mg/kg, oral route) on nociceptive (spontaneous nociception, mechanical and cold allodynia) and inflammatory (paw edema) parameters in pain models involved with TRPA1 activation. Methods: Firstly, it was investigated the ability of Eta to act on TRPA1 or TRPV1 channels (Ca 2+ influx and binding assays in mice spinal cords). Next, it was evaluated the Eta's antinociceptive and anti-inflammatory effects after intraplantar injection of TRPA1 agonists (hydrogen peroxide, cinnamaldehyde or allyl isothiocyanate) in male Swiss mice (30-35 g). Moreover, the Eta's antinociceptive effects were evaluated on complete Freund's adjuvant (CFA)-induced chronic inflammatory pain (CIP), postoperative pain and on paclitaxel-induced peripheral neuropathy (PIPN). Oxidative parameters were evaluated in mice paw utilized for CFA induced-CIP model. Results: Eta inhibited the TRPA1 agonist-induced Ca 2+ influx [I max = 72.4 ± 1.5%; IC 50 = 0.023(0.004-0.125)µg/ ml], but not TRPV1 agonist-induced, nor was able to displace [ 3 H]-resiniferatoxin (TRPV1 agonist) binding. Eta (0.1-100 mg/kg) inhibited the spontaneous nociception [ID 50 = 0.043(0.002-0.723)mg/kg], mechanical [ID 50 = 7.417(1.426-38.570)mg/kg] and cold allodynia, and edema development caused by TRPA1 agonists. Moreover, Eta (100 mg/kg) prevented and reversed the CFA-induced CIP (I max = 55.8 ± 13.7%, I max = 80.4 ± 5.1%, respectively) and postoperative pain (I max = 88.0 ± 11.6%, I max = 51.3 ± 14.9%, respectively), been also effective in reversing the acute (I max = 94.4 ± 12.4%) and chronic (I max = 86.8 ± 8.6%) PIPN. These effects seem to occur by TRPA1 channels pathway, and independently of TRPV1 or oxidative mechanisms. Conclusion: Our results demonstrate that Eta-induced antinociception and anti-inflammatory effects occur by TRPA1 inhibition making possible the use of this preparation as a potential therapeutic agent to treat pathological pains.

Correlation between membrane translocation and analgesic efficacy in kyotorphin derivatives

Biopolymers, 2015

Amidated kyotorphin (L-Tyr-L-Arg-NH 2 ; KTP-NH 2) causes analgesia when systemically administered. The lipophilic ibuprofen-conjugated derivative of KTP-NH 2 has improved analgesic efficacy. However, fast degradation by peptidases impacts negatively in the pharmacodynamics of these drugs. In this work, selected derivatives of KTP and KTP-NH 2 were synthesized to combine lipophilicity and resistance to enzymatic degradation. Eight novel structural modifications were tested for the potential to transverse lipid membranes and to evaluate their efficacy in vivo. The rationale behind the design of the pool of the eight selected molecules consisted in the addition of individual group at the N-terminus, namely the tert-butyloxycarbonyl (Boc), γaminobutyric acid (GABA), acetyl, butanoyl, and propanoyl or in the substitution of the tyrosine residue by an indole moiety and in the replacement of the peptidic bond by a urea-like bond in some cases. All the drugs used in the study are intrinsically fluorescent, which enables the use of spectrofluorimetry to sample the drugs in the permeation assays. The results show that the BOC and indolyl derivatives of KTP-NH 2 have maximal ability to permeate membranes with concomitant maximal analgesic power. Overall, the results demonstrate that membrane permeation is correlated with analgesic efficacy. However, this is not the only factor accounting for analgesia. KTP-NH 2 for instance has low passive permeation but is known to have central action. In this case, hypothetical transcytosis over the blood-brain barrier seems to depend on dipeptide transporters.

Roles of TRPA1 in Pain Pathophysiology and Implications for the Development of a New Class of Analgesic Drugs

The Open Pain Journal, 2013

The Transient Receptor Potential A1 (TRPA1) ion channel has evolved in animals to respond to signals from a variety of sensory stimuli. Many structural determinants of its multimodal activation have been identified to date. TRPA1 activities include responses to exogenous chemical irritants, responses to endogenous inflammatory mediators, zinc, voltage, temperature or stretch and subtle yet critical modulation by calcium ions. TRPA1 has emerged as an important target for several types of pain and inflammatory conditions because of its limited expression profile and its demonstrated roles in mediating different types of pain and sensitization of peripheral sensory afferents. Despite observed species differences in channel pharmacology, recent genetic evidence in human brings some hope that preclinical efficacy in disease models will translate to patient condition. During the past decade, various groups have investigated the development of a new class of analgesic drugs or anti-tussive...

Recent and advanced animal models used in the Screening of analgesics and anti-inflammatory activity

Indian Journal of Pharmaceutical and Biological Research

Non-Steroidal anti-inflammatory drugs (NSAIDs) are consisting of three major anti-pyretic, anti-inflammatory and anti-analgesics properties. They have reduced the sensation of pain, body temperature, and inflammation. It is also used for the treatment of the long-term health problems like arthritis (rheumatoid arthritis, osteoarthritis, and lupus). NSAIDs highly protect the lining of the stomach and intestines from the damaging effects of acid promote blood clotting by activating blood platelets, and promote normal function of the kidney. Incompatible with the action of NSAIDs many different types of drugs and plant use for the treatment of the analgesic, inflammation and pyretic activity. Diclofenac inhibit the cyclooxygenase (COX-2) enzyme with the greater potency that it (COX-1). NSAIDs are generally used in the management of pain because of the integrated role of the COX pathway that is recognition of pyretic, inflammation and analgesic. Introduction to painful procedures and/or...

TRPV1 Antagonists as Analgesic Agents

The Open Pain Journal, 2013

The last decade (2001 - 2010), declared as the Decade of Pain Control and Research by the United States Congress, brought significantly advances in our understanding of pain biology. Unfortunately, this has not translated into additional effective treatments of chronic pain conditions. Chronic pain is a debilitating and complex clinical state usually associated with diabetic neuropathy, postherpetic neuralgia, low back pathology, fibromyalgia, and neurological disorders. Standard pain drugs, even narcotic opioid analgesic agents, often provide unsatisfactory pain relief while causing important side-effect such as sedation, tolerance, dependence, respiratory depression and constipation. Furthermore, the effective management of chronic pain needs a multidisciplinary management approach and still represents one of the most urgent unmet medical need. Recently, preclinical research has uncovered new molecular mechanisms underlying the generation and transduction of pain, many of which re...

TRP channels and monoterpenes: Past and current leads on analgesic properties

Frontiers in Molecular Neuroscience

The activation of the transient receptor potential (TRP) channels expressed by sensory neurons is essential to the transduction of thermal and mechanical sensory information. In the setting of chronic inflammatory conditions, the activation of the melastatin family member 8 (TRPM8), the TRP vanilloid 1 (TRPV1), and the TRP ankyrin 1 (TRPA1) is correlated with pain hypersensitivity reactions. Monoterpenes, among which pulegone and menthol, a major class of phytocompounds present in essential oils of medicinal plants, are known modulators of those TRP channels activity. In the present review, we correlate the monoterpene content of plants with their historical therapeutic properties. We then describe how monoterpenes exert their anti-inflammatory and antihyperalgesia effects through modulation of TRP channels activity. Finally, we discuss the importance and the potential of characterizing new plant extracts and reassessing studied plant extracts for the development of ethnopharmacolog...

The Role of TRP and K+ Ion Channels in Analgesic Effect of NSAIDs

Clinical and Experimental Health Sciences, 2018

YÖNTEMLER: Rutenyum kırmızısı (RR) (3 mg / kg, ip) ve XE 991 (1 mg / kg, ip) varlığında, diklofenak (50 mg / kg, ip), ketoprofen (50 mg / kg, ip), etodolak (70 mg / kg, ip) ve dipironun (500 mg / kg, ip) antinosiseptif etkilerindeki değişiklikler, farelerde sıcak plaka, kuyruk daldırma ve kıvranma testlerinde araştırıldı. BULGULAR: Kuyruk daldırma testinde RR uygulaması sonucu sadece dipiron, etodolak ve ketoprofen'ın analjezik etkisinde anlamlı bir geri dönüş sağlanmıştır. Sıcak plaka testinde ise sadece dipironun analjezik etkisinde belirgin bir geri dönüş görülmektedir. XE 991 uygulanması kuyruk daldırma testinde dipiron ve etodolak'ın etkisinde anlamlı bir geri dönüş sağlarken, ketoprofen ve diklofenak'ın etkisinde göreceli bir geri dönüş sağlamaktadır. Sıcak plaka testinde ise sadece ketoprofen'in analjezik etkisinde anlamlı bir geri dönüş sağlarken, test edilen diğer non-steroidal antiinflamtuvar ilaçların (NSAİİ) etkisinde göreceli bir geri dönüş sağlamaktadır. Writhing testinde ise ne RR uygulamasında ne de XE 991 uygulaması sonucunda önemli bir değişiklik olmamıştır. SONUÇ: Çalışmamızdan elde edilen sonuçlara göre de NSAİİ'ın santral analjezik etkisinde TRP ve potasyum kanal modülasyonun katkısının olabileceğini düşünülmektedir. Bu projede kullanılan ve klinikte ağrı üzerine etkileri bilinen farmakolojik ajanların farklı etki mekanizmalarının aydınlatılmış olması, terapötik yaklaşımlara katkı sağlamakla birlikte yeni ilaç geliştirme çalışmalarında da yol gösterici katkılar sağlayacağı düşünülmektedir. Anahtar kelimeler: NSAİİ, TRP kanalları, potasyum kanalları, analjezi Role of TRP and K + Ion Channels in the Analgesic Effect of NSAIDs ABSTRACT OBJECTIVE: We aimed to clarify the possible contributions of TRP and voltage-dependent K + channels to the analgesic effects of diclofenac, ketoprofen, etodolac, and dipyrone using the nonselective TRP channel blocker ruthenium red and the voltage-dependent K + channel blocker (Kv7; KCNQ) XE 991, respectively. METHODS: We assessed the changes in the antinociceptive effects of diclofenac (50 mg/kg, i.p.), ketoprofen (50 mg/kg, i.p.), etodolac (70 mg/kg, i.p.), and dipyrone (500 mg/kg, i.p.) using ruthenium red (3 mg/kg, i.p.) and XE 991 (1 mg/kg, i.p.) before treatment in the hot plate, tail immersion, and writhing tests in mice. RESULTS: In the tail immersion test, ruthenium red administration resulted in a significant reversal in the analgesic effects of dipyrone, etodolac, and ketoprofen. In the hot plate test, a significant reversal was observed in the analgesic effect of only dipyrone. In the tail immersion test, the administration of XE 991 induced a significant reversal in the analgesic effects of dipyrone and etodolac and a relative reversal in the analgesic effects of ketoprofen and diclofenac. In the hot plate test, XE 991 produced a significant reversal in the analgesic effect of only ketoprofen, whereas it caused a relative reversal in the analgesic effects of other tested nonsteroidal anti-inflammatory drugs (NSAIDs). In the writhing test, no significant change was observed after either XE 991 or ruthenium red administration. CONCLUSIONS: Modulation of TRP and K + channels may be involved in the central analgesic effects of NSAIDs. The clarification of different action mechanisms of NSAIDs will contribute to new therapeutic approaches and provide guidance for new drug development studies.

Demonstration of an anti-hyperalgesic effect of a novel pan-Trk inhibitor PF-06273340 in a battery of human evoked pain models

British Journal of Clinical Pharmacology

Inhibitors of nerve growth factor (NGF) reduce pain in several chronic pain indications. NGF signals through tyrosine kinase receptors of the tropomyosin-related kinase (Trk) family and the unrelated p75 receptor. PF-06273340 is a small molecule inhibitor of Trks A, B and C that reduces pain in nonclinical models, and the present study aimed to investigate the pharmacodynamics of this first-in-class molecule in humans. METHODS A randomized, double-blind, single-dose, placebo-and active-controlled five-period crossover study was conducted in healthy human subjects (NCT02260947). Subjects received five treatments: PF-06273340 50 mg, PF-06273340 400 mg, pregabalin 300 mg, ibuprofen 600 mg and placebo. The five primary endpoints were the pain detection threshold for the thermal pain tests and the pain tolerance threshold for the cold pressor, electrical stair and pressure pain tests. The trial had predefined decision rules based on 95% confidence that the PF-06273340 effect was better than that of placebo. RESULTS Twenty subjects entered the study, with 18 completing all five periods. The high dose of PF-06273340 met the decision rules on the ultraviolet (UV) B skin thermal pain endpoint [least squares (LS) mean vs. placebo: 1.13, 95% confidence interval: 0.64-1.61], but not on the other four primary endpoints. The low dose did not meet the decision criteria for any of the five primary endpoints. Pregabalin (cold pressor and electrical stair tests) and ibuprofen (UVB thermal pain) showed significant analgesic effects on expected endpoints. CONCLUSIONS The study demonstrated, for the first time, the translation of nonclinical effects into man in an inflammatory pain analgesic pharmacodynamic endpoint using a pan-Trk inhibitor.