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• W4377019984 abstract "Abstract The psychedelic compound psilocybin has shown therapeutic benefit in the treatment of numerous psychiatric diseases. A recent randomized clinical trial conducted at Johns Hopkins Bayview Medical Center demonstrated the efficacy of psilocybin-assisted therapy in the treatment of Major Depressive Disorder (MDD). Similarly, a phase IIb study evaluating psilocybin-assisted therapy for treatment-resistant depression (TRD) presented statistically meaningful and long-term reduction in depressive symptoms. Also, many studies have reported the successful treatment of severe anxiety after a single oral dose of psilocybin, especially in patients struggling with cancer-related distress (CRD). Despite these compelling clinical results, concerns regarding the duration of the psychedelic experience produced by psilocybin pose a significant barrier to its widespread therapeutic application. Psilocybin, derived from magic mushrooms is the naturally occurring prodrug of the neuroactive compound psilocin. When orally administered, exposure to the acidic gastrointestinal (GI) environment together with enzymatic processing by intestinal and hepatic alkaline phosphatase lead to the dephosphorylation of psilocybin producing elevated levels of systemic psilocin. These plasma levels are detectable up to 24 h and produce a psychoactive episode lasting as long as 6 h post-ingestion. In order to positively modify the kinetics of the acute psychedelic response, we have engineered a library of novel prodrug derivatives (NPDs) of psilocin, introducing a diversity of alternative metabolically cleavable moieties modified at the 4-carbon position of the core indole ring. This library consists of twenty-eight unique compounds represented by nine distinct prodrug classes. Each molecule was screened in vitro for metabolic stability using isolated human serum, and human cellular fractions derived from liver and intestinal tissues. This screen revealed fifteen prodrugs that produced measurable levels of psilocin in vitro , with ester and thiocarbonate-based prodrug derivatives significantly represented. These fifteen NPDs were further evaluated for pharmacokinetic (PK) profiles in mice, assessing plasma levels of both residual prodrug and resultant psilocin. PK results confirmed the efficiency of ester and thiocarbonate-based prodrug metabolism upon oral and intravenous administration, achieving levels reduced, albeit comparable to levels of psilocybin-derived psilocin. Of note, almost all NPDs tested maintained reduced overall exposure of psilocin relative to psilocybin, with no measurable levels detected at 24 h post-dose. Finally, all NPDs were screened for CNS bioavailability in healthy mice using the Head Twitch Response (HTR), a behavioural biomarker of 5-HT 2A receptor stimulation and an established proxy for psychoactive potential. Interestingly, five NPDs produced peak HTR that approached or exceeded levels induced by an equivalent dose of psilocybin. Among these bioactive prodrugs, an ester-based and thiocarbonate-based molecule produced long-term anxiolytic benefit in chronically stressed mice evaluated in the marble burying psychiatric model. Overall, this screening campaign identified novel candidate prodrugs of psilocin with altered metabolic profiles and reduced pharmacological exposure, potentially attenuating the duration of the psychedelic response. These molecules still maintained the long-term psychiatric and physiological benefits characteristic of psilocybin therapy. Additionally, these modified parameters also offer the opportunity for altered routes of administration bypassing conventional oral dosing." @default.
• W4377019984 created "2023-05-19" @default.
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• W4377019984 date "2023-05-18" @default.
• W4377019984 modified "2023-09-27" @default.
• W4377019984 title "Novel psilocin prodrugs with altered pharmacological properties as candidate therapies for treatment-resistant anxiety disorders" @default.
• W4377019984 cites W1964253779 @default.
• W4377019984 cites W1977430165 @default.
• W4377019984 cites W1981707861 @default.
• W4377019984 cites W1982309599 @default.
• W4377019984 cites W1992103170 @default.
• W4377019984 cites W1995013188 @default.
• W4377019984 cites W2009134620 @default.
• W4377019984 cites W2010427019 @default.
• W4377019984 cites W2012266823 @default.
• W4377019984 cites W2015496429 @default.
• W4377019984 cites W2017494021 @default.
• W4377019984 cites W2018420238 @default.
• W4377019984 cites W2020472715 @default.
• W4377019984 cites W2021263341 @default.
• W4377019984 cites W2031480693 @default.
• W4377019984 cites W2031832463 @default.
• W4377019984 cites W2038839611 @default.
• W4377019984 cites W2041036432 @default.
• W4377019984 cites W2045595011 @default.
• W4377019984 cites W2054823071 @default.
• W4377019984 cites W2056039433 @default.
• W4377019984 cites W2057355532 @default.
• W4377019984 cites W2059183805 @default.
• W4377019984 cites W2059976461 @default.
• W4377019984 cites W2066457796 @default.
• W4377019984 cites W2067481209 @default.
• W4377019984 cites W2069122038 @default.
• W4377019984 cites W2080093346 @default.
• W4377019984 cites W2084145610 @default.
• W4377019984 cites W2085139899 @default.
• W4377019984 cites W2096626991 @default.
• W4377019984 cites W2102333760 @default.
• W4377019984 cites W2121441663 @default.
• W4377019984 cites W2131257415 @default.
• W4377019984 cites W2154105276 @default.
• W4377019984 cites W2155081002 @default.
• W4377019984 cites W2158178436 @default.
• W4377019984 cites W2161555895 @default.
• W4377019984 cites W2187761001 @default.
• W4377019984 cites W2327221240 @default.
• W4377019984 cites W2396675581 @default.
• W4377019984 cites W2411998515 @default.
• W4377019984 cites W2414768696 @default.
• W4377019984 cites W2490235167 @default.
• W4377019984 cites W2558412547 @default.
• W4377019984 cites W2559739670 @default.
• W4377019984 cites W2572835720 @default.
• W4377019984 cites W2584769666 @default.
• W4377019984 cites W2600624779 @default.
• W4377019984 cites W2604652480 @default.
• W4377019984 cites W2610144880 @default.
• W4377019984 cites W2779452853 @default.
• W4377019984 cites W2781316183 @default.
• W4377019984 cites W2789372961 @default.
• W4377019984 cites W2791704659 @default.
• W4377019984 cites W2801859295 @default.
• W4377019984 cites W2904597631 @default.
• W4377019984 cites W2914255920 @default.
• W4377019984 cites W2946341151 @default.
• W4377019984 cites W2988070888 @default.
• W4377019984 cites W2999364864 @default.
• W4377019984 cites W3000430699 @default.
• W4377019984 cites W3015140823 @default.
• W4377019984 cites W3016937424 @default.
• W4377019984 cites W3037055231 @default.
• W4377019984 cites W3045160853 @default.
• W4377019984 cites W3096208965 @default.
• W4377019984 cites W3112700248 @default.
• W4377019984 cites W3129221857 @default.
• W4377019984 cites W3134320342 @default.
• W4377019984 cites W3155245221 @default.
• W4377019984 cites W3156937150 @default.
• W4377019984 cites W4200256717 @default.
• W4377019984 cites W4206987579 @default.
• W4377019984 cites W4212903385 @default.
• W4377019984 cites W4225114051 @default.
• W4377019984 cites W4248107770 @default.
• W4377019984 cites W4292454698 @default.
• W4377019984 cites W561083445 @default.
• W4377019984 doi "https://doi.org/10.1101/2023.05.16.540994" @default.

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