Metabolic instability vs fibre recruitment contribution to the $${\dot{V}O_2}$$ slow component in different exercise intensity domains

This study focused on the steady-state phase of exercise to evaluate the relative contribution of metabolic instability (measured with NIRS and haematochemical markers) and muscle activation (measured with EMG) to the oxygen consumption ($${\dot{V}O_2}$$ V ˙ O 2 ) slow component ($${\dot{V}O_2}{_s}{_c}$$ V ˙ O 2 s c ) in different intensity domains. We hypothesized that (i) after the transient phase, $${\dot{V}O_2}$$ V ˙ O 2 , metabolic instability and muscle activation tend to increase differently over time depending on the relative exercise intensity and (ii) the increase in $${\dot{V}O_2}{_s}{_c}$$ V ˙ O 2 s c is explained by a combination of metabolic instability and muscle activation. Eight active men performed a constant work rate trial of 9 min in the moderate, heavy and severe intensity domains. $${\dot{V}O_2}$$ V ˙ O 2 , root mean square by EMG (RMS), deoxyhaemoglobin by NIRS ([HHb]) and haematic markers of metabolic stability (i.e. [La−], pH, HCO3−) were measured. The physiological responses in different intensity domains were compared by two-way RM-ANOVA. The relationships between the increases of [HHb] and RMS with $${\dot{V}O_2}$$ V ˙ O 2 after the third min were compared by simple and multiple linear regressions. We found domain-dependent dynamics over time of $${\dot{V}O_2}$$ V ˙ O 2 , [HHb], RMS and the haematic markers of metabolic instability. After the transient phase, the rises in [HHb] and RMS showed medium–high correlations with the rise in $${\dot{V}O_2}$$ V ˙ O 2 ([HHb] r = 0.68, p < 0.001; RMS r = 0.59, p = 0.002). Moreover, the multiple linear regression showed that both metabolic instability and muscle activation concurred to the $${\dot{V}O_2}{_s}{_c}$$ V ˙ O 2 s c (r = 0.75, [HHb] p = 0.005, RMS p = 0.042) with metabolic instability possibly having about threefold the relative weight compared to recruitment. Seventy-five percent of the dynamics of the $${\dot{V}O_2}{_s}{_c}$$ V ˙ O 2 s c was explained by [HHb] and RMS.

An Anthrone-Based Kv7.2/7.3 Channel Blocker with Improved Properties for the Investigation of Psychiatric and Neurodegenerative Disorders

A set of novel Kv7.2/7.3 (KCNQ2/3) channel blockers was synthesized to address several liabilities of the known compounds XE991 (metabolic instability and CYP inhibition) and the clinical compound DMP 543 (acid instability, insolubility, and lipophilicity). Using the anthrone scaffold of the prior channel blockers, alternative heteroarylmethyl substituents were installed via enolate alkylation reactions. Incorporation of a pyridazine and a fluorinated pyridine gave an analog (JDP-107) with an optimal combination of potency (IC₅₀= 0.16 𝜇M in a Kv7.2 thallium flux assay), efficacy in a Kv7.2/7.3 patch clamp assay, and drug-like properties.

An Anthrone-Based Kv7.2/7.3 Channel Blocker with Improved Properties for the Investigation of Psychiatric and Neurodegenerative Disorders

A set of novel Kv7.2/7.3 (KCNQ2/3) channel blockers was synthesized to address several liabilities of the known compounds XE991 (metabolic instability and CYP inhibition) and the clinical compound DMP 543 (acid instability, insolubility, and lipophilicity). Using the anthrone scaffold of the prior channel blockers, alternative heteroarylmethyl substituents were installed via enolate alkylation reactions. Incorporation of a pyridazine and a fluorinated pyridine gave an analog (JDP-107) with an optimal combination of potency (IC₅₀= 0.16 𝜇M in a Kv7.2 thallium flux assay), efficacy in a Kv7.2/7.3 patch clamp assay, and drug-like properties.