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So far we have amentoflavone and caffeine; here are some additional ingredients in Uncut- I am saving some of the best for last:
-Huperzine A (from Huperzia serrata)
Bioavailability- high; logP 2.02
Onset- 5-10 minutes
Tᵐᵃᵡ-60 minutes
A potent, reversible, and selective inhibitor of Acetylcholine esterase (AChE), an enzyme that converts acetylcholine into acetate and choline. Huperzine A possesses very high bioavailability, and can cross the Blood-Brain Barrier (BBB) readily. First discovered in the early 80’s, structure activity relationship (SAR studies) have shown that Huperzine A possesses a longer duration of activity and a higher therapeutic index than many pharmaceutical AChE inhibitors. Computer-generated superposition of Huperzine A and ACh show that Hup A contains the same basic structural characteristics of ACh (7); there is a reasonable structural similarity between the nitrogen, carbonyl, and oxygen that is present in ACh, and the amino nitrogen, nitrogen, and oxygen in Hup A (4). Most of the SAR research has been on potential alterations of this 5-aminomethyl-2(1H)-pyridone part of Huperzine A- so it can most likely be considered a pharmacophoric moiety for the inhibition of AChE (a pharmacophore is a spatial arrangement of functional groups necessary for biological activity)(13). Ashani et al. (1992) demonstrated a very slow dissociation rate in solution of the Huperzine A/AChE complex, without any detectable chemical modification in the inhibitor; this demonstrates a strong resistance to metabolism as an AChE-binding agent (1). By inhibiting AChE, Huperzine A increases acetylcholine in the central and peripheral nervous systems (CNS and PNS), and acetylcholine levels in the PNS are a major rate-limiting step in contractile activity in skeletal muscle (along with calcium release from the sarcoplasmic reticulum)(16). This may explain some of the positive effects of Uncut™ on increased muscular contractility, as acetylcholine acts as an excitatory neurotransmitter at the neuromuscular junction (NMJ), and the production and availability of acetylcholine tend to be limiting factors in muscular contraction at the NMJ.
Naringin (Citrus paradisi macfaydven)-
Bioavailability- moderate; logP -0.16
Onset- 15-20 minutes
Tᵐᵃᵡ- 180 minutes
A citrus bioflavanoid, naringin has been reported to change the pharmacokinetics of a wide variety of drugs due to the inhibition of the metabolizing cytochrome P450 (CYP) 3A enzymes, a barrier protein for drug absorption. Naringin has been shown to significantly alter the pharmacokinetics of caffeine and PDE5 inhibitors such as slidenafil, increasing the bioavailability of these compounds; naringin has also been shown to have some p-glycoprotein inhibitory characteristics. P-glycoprotein (p-gp) is an efflux protein found in the intestines that is responsible for the removal of compounds from target cells; p-glycoprotein is strongly associated with MDR (multi-drug resistance), a condition in which decreased levels of drugs (or supplements) accumulate within target cells. By inhibiting p-glycoprotein, an alteration in the AUC of many different co-ingested drugs (and supplements) has been observed; Ali et al. (2009) found that naringin had a modulatory effect on the expression of p-gp and a trapping effect when naringin was ingested concurrently with anti-mestatic drugs; Dahan et al. (2009) found that naringin can significantly increase the oral bioavailability of colchicine (similar in structure to higenamine) through decreasing p-gp expression and MDR. This effect could potentially carry over to higenamine due to similarities in structure (but not function) between the two ingredients; a similar study by Shirasaka et al. (2009) found that the co-ingestion of naringin and a β-AR₁-antagonist (talinolol) significantly altered the bioavailability of talinolol through a change in p-gp expression.
-Chlorogenic Acid (from Green Coffee Bean)-
Bioavailability- moderate; logP -0.27
Onset- 5-10 minutes
Tᵐᵃᵡ-35 minutes
Catechol-containing phenol from coffee; strong inhibitor of Catechol-O-Methyltransferase (COMT, an enzyme that metabolizes catecholamines and other catechol structures), as evidenced in study by Zhu et al. (2008), who found “chlorogenic acid, caffeic acid, and caffeic acid phenethyl ester (three catechol-containing polyphenols richly present in coffee)….. are highly effective inhibitors for the human liver and placental COMT-mediated O-methylation of catechol estrogens in vitro….. computational values showed that the binding energy of chlorogenic acid was much lower than caffeic acid, which suggests that the binding affinity of the former was much higher than the latter and the competitive component of COMT inhibition would be stronger by chlorogenic acid than caffeic acid…..it is expected that collectively these coffee polyphenols may provide a biologically-meaningful inhibition of the O-methylation of various endogenous catechols in vivo. It will be of interest to determine in human subjects the extent of inhibition of the metabolic methylation of endogenously-formed catechol estrogens and possibly other endogenous catechol substrates (such as catecholamines).(41)” COMT is the major enzyme that metabolizes higenamine via the hydroxyl structures on the tetrahydroisoquinolone moeity; hydroxylation at C6 is necessary for adrenergic binding of higenamine. A study by Kimura (1989) found that higenamine had positive inotropic effects (a sign of adrenergic binding), while R-Coclaurine and S-Reticuline (similar structures, but are methylated @ C6) had opposite effects, indicating an inhibitory effect on adrenergic binding via the methylation that normally occurs during higenamine metabolism (42,50). Uncut™ seeks to prolong the action of higenamine by inhibiting COMT via chlorogenic acid, thus keeping C6 intact for a longer period of time(42).
-Huperzine A (from Huperzia serrata)
Bioavailability- high; logP 2.02
Onset- 5-10 minutes
Tᵐᵃᵡ-60 minutes
A potent, reversible, and selective inhibitor of Acetylcholine esterase (AChE), an enzyme that converts acetylcholine into acetate and choline. Huperzine A possesses very high bioavailability, and can cross the Blood-Brain Barrier (BBB) readily. First discovered in the early 80’s, structure activity relationship (SAR studies) have shown that Huperzine A possesses a longer duration of activity and a higher therapeutic index than many pharmaceutical AChE inhibitors. Computer-generated superposition of Huperzine A and ACh show that Hup A contains the same basic structural characteristics of ACh (7); there is a reasonable structural similarity between the nitrogen, carbonyl, and oxygen that is present in ACh, and the amino nitrogen, nitrogen, and oxygen in Hup A (4). Most of the SAR research has been on potential alterations of this 5-aminomethyl-2(1H)-pyridone part of Huperzine A- so it can most likely be considered a pharmacophoric moiety for the inhibition of AChE (a pharmacophore is a spatial arrangement of functional groups necessary for biological activity)(13). Ashani et al. (1992) demonstrated a very slow dissociation rate in solution of the Huperzine A/AChE complex, without any detectable chemical modification in the inhibitor; this demonstrates a strong resistance to metabolism as an AChE-binding agent (1). By inhibiting AChE, Huperzine A increases acetylcholine in the central and peripheral nervous systems (CNS and PNS), and acetylcholine levels in the PNS are a major rate-limiting step in contractile activity in skeletal muscle (along with calcium release from the sarcoplasmic reticulum)(16). This may explain some of the positive effects of Uncut™ on increased muscular contractility, as acetylcholine acts as an excitatory neurotransmitter at the neuromuscular junction (NMJ), and the production and availability of acetylcholine tend to be limiting factors in muscular contraction at the NMJ.
Naringin (Citrus paradisi macfaydven)-
Bioavailability- moderate; logP -0.16
Onset- 15-20 minutes
Tᵐᵃᵡ- 180 minutes
A citrus bioflavanoid, naringin has been reported to change the pharmacokinetics of a wide variety of drugs due to the inhibition of the metabolizing cytochrome P450 (CYP) 3A enzymes, a barrier protein for drug absorption. Naringin has been shown to significantly alter the pharmacokinetics of caffeine and PDE5 inhibitors such as slidenafil, increasing the bioavailability of these compounds; naringin has also been shown to have some p-glycoprotein inhibitory characteristics. P-glycoprotein (p-gp) is an efflux protein found in the intestines that is responsible for the removal of compounds from target cells; p-glycoprotein is strongly associated with MDR (multi-drug resistance), a condition in which decreased levels of drugs (or supplements) accumulate within target cells. By inhibiting p-glycoprotein, an alteration in the AUC of many different co-ingested drugs (and supplements) has been observed; Ali et al. (2009) found that naringin had a modulatory effect on the expression of p-gp and a trapping effect when naringin was ingested concurrently with anti-mestatic drugs; Dahan et al. (2009) found that naringin can significantly increase the oral bioavailability of colchicine (similar in structure to higenamine) through decreasing p-gp expression and MDR. This effect could potentially carry over to higenamine due to similarities in structure (but not function) between the two ingredients; a similar study by Shirasaka et al. (2009) found that the co-ingestion of naringin and a β-AR₁-antagonist (talinolol) significantly altered the bioavailability of talinolol through a change in p-gp expression.
-Chlorogenic Acid (from Green Coffee Bean)-
Bioavailability- moderate; logP -0.27
Onset- 5-10 minutes
Tᵐᵃᵡ-35 minutes
Catechol-containing phenol from coffee; strong inhibitor of Catechol-O-Methyltransferase (COMT, an enzyme that metabolizes catecholamines and other catechol structures), as evidenced in study by Zhu et al. (2008), who found “chlorogenic acid, caffeic acid, and caffeic acid phenethyl ester (three catechol-containing polyphenols richly present in coffee)….. are highly effective inhibitors for the human liver and placental COMT-mediated O-methylation of catechol estrogens in vitro….. computational values showed that the binding energy of chlorogenic acid was much lower than caffeic acid, which suggests that the binding affinity of the former was much higher than the latter and the competitive component of COMT inhibition would be stronger by chlorogenic acid than caffeic acid…..it is expected that collectively these coffee polyphenols may provide a biologically-meaningful inhibition of the O-methylation of various endogenous catechols in vivo. It will be of interest to determine in human subjects the extent of inhibition of the metabolic methylation of endogenously-formed catechol estrogens and possibly other endogenous catechol substrates (such as catecholamines).(41)” COMT is the major enzyme that metabolizes higenamine via the hydroxyl structures on the tetrahydroisoquinolone moeity; hydroxylation at C6 is necessary for adrenergic binding of higenamine. A study by Kimura (1989) found that higenamine had positive inotropic effects (a sign of adrenergic binding), while R-Coclaurine and S-Reticuline (similar structures, but are methylated @ C6) had opposite effects, indicating an inhibitory effect on adrenergic binding via the methylation that normally occurs during higenamine metabolism (42,50). Uncut™ seeks to prolong the action of higenamine by inhibiting COMT via chlorogenic acid, thus keeping C6 intact for a longer period of time(42).
