Identification and Characterization of GAL-021 as a Novel Breathing Control Modulator

Abstract

GAL-021 behaved as a breathing control modulator in rodents and nonhuman primates and diminished opioid-induced respiratory depression without compromising opioid analgesia. It acted predominantly at the carotid body, in part by inhibiting KCa1.1 channels. Its preclinical profile qualified the compound to enter clinical trials to assess effects on breathing control disorders such as drug (opioid)-induced respiratory depression and sleep apnea.

High Efficacy by GAL-021: A Known Intravenous Peripheral Chemoreceptor Modulator that Suppresses BKCa-Channel Activity and Inhibits IK(M) or Ih

“…GAL-021 treatment is noted to have a short duration of action after a bolus injection [1,52]. The major effect of GAL-021 on ionic currents (e.g., I K(Ca) or I K(M) ) shown here also had a rapid onset of action.…”

“…GAL-021 has recently been developed as a novel breathing control modulator thought to preserve respiratory drive and to protect patients from the respiratory impairment resulting from opioids and other modalities; moreover, it notably did not influence analgesia [1][2][3][4][5][6][7]. The studies have also reported that this agent is an experimental drug demonstrated to inhibit Ca 2+ -activated K + channels with big conductance functionally expressed on type 1 cells of the carotid bodies [1,8,9]. However, to what extent this compound perturbs other patterns of voltage-gated ionic currents has not yet been determined.…”

“…Because of the large conductance, BK Ca channel is also known as maxi-or big-K channel. BK Ca channels, which are functionally expressed in a variety of cells, can play substantial roles in physiological and pathophysiological events including neurotransmitter release, muscle relaxation, and oxygen sensing in chemoreceptor cells [1,8,[10][11][12][13][14][15][16][17][18][19]. It is also noted that BMS-204352 (MaxiPost TM ), an activator of BK Ca channels, could activate a voltage-independent KCNQ4-encoded current [20,21].…”

“…Active respiratory neurons were previously reported to functionally express HCN channels [32][33][34]. However, little information is available regarding the underlying mechanism of actions of GAL-021 or other related compounds on different types of ionic currents (e.g., I K(M) and I h ) present in endocrine or neuroendocrine cells, or central mammalian neurons, although it was previously reported to suppress the activity of BK Ca channels in type 1 cells of the carotid bodies [1]. Therefore, in this study, we wanted to investigate the ionic mechanisms by which the presence of GAL-021 is able to interact functionally with ion channels, thereby producing any clear modifications on macroscopic ionic currents identified in pituitary GH 3 cells.…”

Characterization of Effectiveness in Concerted Ih Inhibition and IK(Ca) Stimulation by Pterostilbene (Trans-3,5-dimethoxy-4′-hydroxystilbene), a Stilbenoid

“…As summarized in Figure 7B, in the continued presence of 3 µM PTER, subsequent addition of neither TRAM-39 (3 µM) nor tolbutamide (10 µM) substantially modified PTER-mediated elevation in the channel opening probability, while that of verrculogen (1 µM) or GAL-021 (10 µM) was capable of reversing the PTER-induced raise in channel activity. GAL-021 is recognized as an intravenous inhibitor of BK Ca channels [54]. For example, further application of GAL-021 (10 µM), but still in the presence of PTER (3 µM), attenuated channel activity from 0.084 ± 0.012 to 0.037 ± 0.009 (n = 8, p < 0.05).…”