Fifteen years of Na V 1.7 channels as an analgesic target: Why has excellent in vitro pharmacology not translated into in vivo analgesic efficacy?

Abstract Design, Synthesis, and Pharmacological Evaluation of Ultrashort- to Long-acting Opioid Analgetics. By Feldman PL, James MK, Brackeen MF, Bilotta JM, Schuster SV, Lahey AP, Lutz MW, Johnson MR, Leighton HJ. J Med Chem 1991; 34:2202-8. Copyright 1991 American Chemical Society. Reprinted with permission. In an effort to discover a potent ultrashort-acting µ-opioid analgetic that is capable of metabolizing to an inactive species independent of hepatic function, several classes of 4-anilidopiperidine analgetics were synthesized and evaluated. One series of compounds displayed potent µ-opioid agonist activity with a high degree of analgesic efficacy and an ultrashort to long duration of action. These analgetics, 4-(methoxycarbonyl)-4-[1-oxopropyl)phenylamino]-1-piperidinepropanoic acid alkyl esters, were evaluated in vitro in the guinea pig ileum for µ-opioid activity, in vivo in the rat tail withdrawal assay for analgesic efficacy and duration of action, and in vitro in human whole blood for their ability to be metabolized in blood. Compounds in this series were all shown to be potent µ agonists in vitro, but depending upon the alkyl ester substitution, the potency and duration of action in vivo varied substantially. The discrepancies between the in vitro and in vivo activities and variations in duration of action are probably due to different rates of ester hydrolysis by blood esterase(s). The [structure–activity relationships] with respect to analgesic activity and duration of action as a function of the various esters synthesized is discussed. It was also demonstrated that the duration of action for the ultrashort-acting analgetic, 8, does not change upon prolonged infusion or administration of multiple bolus injections.

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Partial agonist activity of R3(BΔ23–27)R/I5 at RXFP3 – Investigation of in vivo and in vitro pharmacology

European Journal of Pharmacology ◽

10.1016/j.ejphar.2014.11.041 ◽

2015 ◽

Vol 747 ◽

pp. 123-131 ◽

Cited By ~ 1

Author(s):

Lisbeth Kristensson ◽

Gaëll Mayer ◽

Karolina Ploj ◽

Martina Wetterlund ◽

Susanne Arlbrandt ◽

...

Keyword(s):

Partial Agonist ◽

Agonist Activity ◽

Partial Agonist Activity ◽

In Vitro Pharmacology

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L-750355, a human ß3-adrenoceptor agonist; in vitro pharmacology and profile of activity in vivo in the rhesus monkey

European Journal of Pharmacology ◽

10.1016/s0014-2999(00)00724-x ◽

2000 ◽

Vol 407 (1-2) ◽

pp. 175-181 ◽

Cited By ~ 3

Author(s):

Michael J Forrest ◽

Gary Hom ◽

Tom Bach ◽

Mari Rios Candelore ◽

Margaret A Cascieri ◽

...

Keyword(s):

Rhesus Monkey ◽

Adrenoceptor Agonist ◽

In Vitro Pharmacology

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Mechanism of baricitinib supports artificial intelligence-predicted testing in COVID-19 patients

10.21203/rs.3.rs-23195/v1 ◽

2020 ◽

Cited By ~ 3

Author(s):

Justin Stebbing ◽

Venkatesh Krishnan ◽

Stephanie de Bono ◽

Silvia Ottaviani ◽

Giacomo Casalini ◽

...

Keyword(s):

Artificial Intelligence ◽

Case Series ◽

Janus Kinase ◽

Rapid Decline ◽

Health Crisis ◽

Viral Propagation ◽

Jak2 Inhibitor ◽

In Vitro Pharmacology

Abstract Baricitinib, is an oral Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of rheumatoid arthritis (RA) that was independently hypothesized, using artificial intelligence (AI)-algorithms, to be useful for the treatment of COVID-19 infection via a proposed anti-cytokine effects and as an inhibitor of host cell viral propagation1,2. We validated the AI-predicted biochemical inhibitory effects of baricitinib on human numb-associated kinase (hNAK) members measuring nanomolar affinities for AAK1, BIKE, and GAK. Inhibition of NAKs led to reduced viral infectivity with baricitinib using human primary liver spheroids, which express hAAK1 and hGAK. We evaluated the in vitro pharmacology of baricitinib across relevant leukocyte subpopulations coupled to its in vivo pharmacokinetics and showed it inhibited signaling of cytokines implicated in COVID-19 infection. In a case series of patients with bilateral COVID-19 pneumonia, baricitinib treatment was associated with clinical and radiologic recovery, a rapid decline in SARS-CoV-2 viral load, inflammatory markers, and IL-6 levels. This represents an important example of an AI-predicted treatment showing scientific and clinical promise during a global health crisis. Collectively, these data support further evaluation of the AI-derived hypothesis on anti-cytokine and anti-viral activity and supports its assessment in randomized trials in hospitalized COVID-19 patients.

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Nav1.7 target modulation and efficacy can be measured in nonhuman primate assays

Science Translational Medicine ◽

10.1126/scitranslmed.aay1050 ◽

2021 ◽

Vol 13 (594) ◽

pp. eaay1050

Author(s):

Richard L. Kraus ◽

Fuqiang Zhao ◽

Parul S. Pall ◽

Dan Zhou ◽

Joshua D. Vardigan ◽

...

Keyword(s):

Plasma Concentration ◽

Clinical Studies ◽

Clinical Success ◽

Rhesus Macaques ◽

Phase 1 ◽

Analgesic Efficacy ◽

Loss Of Function ◽

Noxious Heat

Humans with loss-of-function mutations in the Nav1.7 channel gene (SCN9A) show profound insensitivity to pain, whereas those with gain-of-function mutations can have inherited pain syndromes. Therefore, inhibition of the Nav1.7 channel with a small molecule has been considered a promising approach for the treatment of various human pain conditions. To date, clinical studies conducted using selective Nav1.7 inhibitors have not provided analgesic efficacy sufficient to warrant further investment. Clinical studies to date used multiples of in vitro IC50 values derived from electrophysiological studies to calculate anticipated human doses. To increase the chance of clinical success, we developed rhesus macaque models of action potential propagation, nociception, and olfaction, to measure Nav1.7 target modulation in vivo. The potent and selective Nav1.7 inhibitors SSCI-1 and SSCI-2 dose-dependently blocked C-fiber nociceptor conduction in microneurography studies and inhibited withdrawal responses to noxious heat in rhesus monkeys. Pharmacological Nav1.7 inhibition also reduced odor-induced activation of the olfactory bulb (OB), measured by functional magnetic resonance imaging (fMRI) studies consistent with the anosmia reported in Nav1.7 loss-of-function patients. These data demonstrate that it is possible to measure Nav1.7 target modulation in rhesus macaques and determine the plasma concentration required to produce a predetermined level of inhibition. The calculated plasma concentration for preclinical efficacy could be used to guide human efficacious exposure estimates. Given the translatable nature of the assays used, it is anticipated that they can be also used in phase 1 clinical studies to measure target modulation and aid in the interpretation of phase 1 clinical data.

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In vivo and in vitro pharmacology of SR48,968 as tachykinin NK-2 receptor antagonist

Regulatory Peptides ◽

10.1016/0167-0115(92)90918-k ◽

1992 ◽

Vol 37 ◽

pp. S63

Author(s):

S. Giuliani ◽

R. Patacchini ◽

A. Giachetti ◽

C.A. Maggi

Keyword(s):

Receptor Antagonist ◽

In Vitro Pharmacology

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ADRB2, pain and opioids in mice and man

Scandinavian Journal of Pain ◽

10.1016/j.sjpain.2016.05.016 ◽

2016 ◽

Vol 12 (1) ◽

pp. 122-122

Author(s):

O. Kambur ◽

A. Samoshkin ◽

M. Kaunisto ◽

J.S. Wieskopf ◽

J.S. Mogil ◽

...

Keyword(s):

Molecular Mechanism ◽

Cellular Localization ◽

Analgesic Efficacy ◽

Breast Cancer Surgery ◽

Cold Pain ◽

Cellular Effects ◽

Ici 118,551 ◽

Opioid Induced Hyperalgesia

Abstract Aims We aim to characterize the effects of variation within ADRB2-gene on pain and opioid requirements in human patients. We will assess ADRB2-OPRM1-6TM heterodimer as a molecular mechanism, potentially explaining pronociceptive and antianalgetic effects, using preclinical in vitro and in vivo models. We will further assess clinical significance via its genetic proxy, rs563649 in humans Methods In humans, experimental and postoperative pain and opioid responses were assessed in 1000 breast cancer surgery patients. Association of ADRB2 (n = 40) and OPRM1 (n = 1) polymorphisms was assessed using linear regression and analysis of variances (ANOVA). In vitro methods involved immunofluorescence microscopy (IF), cellular localization and translocation of 6TM/β2AR-heterodimers and Ca2+-measurements. Behavioral in vivo characterization was performed in mice using formalin, von Frey, hot plate and cold plate tests after administration of morphine, specific OPRM1-6TM agonist IBNtxA and ADRB2-antagonist ICI118,551. Results In humans, several ADRB2 SNPs were associated with pain and opioid phenotypes. The strongest associations were seen between cold pain phenotypes and rs17108817 & rs11957757 (p < 0.0001). In vitro, coexpression with β2-Ars increased translocation of 6TM-MOR to plasma membrane and Ca2+responses after treatment with selective 6TM-agonist, IBNtxA, compared with the cells expressing OPRM1-6TM alone. In vivo, co-administration of P2AR selective antagonist ICI 118,551 increased analgesic efficacy of opioids in a synergistic manner and reduced opioid-induced hyperalgesia. Conclusions Our findings suggest that ADRB2 and genetic variation in ADRB2-gene are involved in the modulation of human pain and opioid responses. 6TM-MOR/P2-AR heterodimerization represents a molecular mechanism causing excitatory cellular effects and sufficient explanatory potential to explain pronociceptive and antianalgesic effects. Our animal findings further confirmed the concept of β2-AR and 6TM-MOR interaction in vivo. We suggest that co-administration of β-blockers with opioids might increase efficacy and safety of OPRM1 agonists.

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