Design, Synthesis, and Evaluation of a Novel 4-Aminomethyl-4-fluoropiperidine as a T-Type Ca²⁺Channel Antagonist

Abstract

The novel T-type antagonist ( S)- 5 has been prepared and evaluated in in vitro and in vivo assays for T-type calcium ion channel activity. Structural modification of the piperidine leads 1 and 2 afforded the fluorinated piperidine ( S)- 5, a potent and selective antagonist that displayed in vivo CNS efficacy without adverse cardiovascular effects.

Antagonism of T-type calcium channels inhibits high-fat diet–induced weight gain in mice

“…When fed normal chow, WT and KO animals did not show significant differences in feed efficiency (4.6 ± 8.5 mg/kcal vs. 11.9 ± 9.5 mg/kcal; P = 0.58, unpaired 2-tailed Student's t test). However, when fed HFD, WT animals had significantly higher feed efficiency than did their KO littermates (28.1 ± 2.9 mg/kcal vs. 8.8 ± 3.3 mg/kcal; functional Ca 2+ flux assays was determined as described previously (37). Potency is shown as the inflection point from a 4-parameter sigmoidal fit to the data.…”

“…Therefore, we initiated a medicinal chemistry effort to distinguish potent, selective and pharmacokinetically favorable T-type calcium channel antagonists and identified T-type antagonist-A2 (TTA-A2). TTA-A2 is a selective, potent, and state-dependent T-type calcium channel antagonist, for which functional cell-based fluorescence assays (37) showed a potency of 9.4 ± 4.4 nM (n = 7) in the depolarized (inactivated) state and a potency of 384 ± 266 nM (n = 8) in hyperpolarized (closed) state (Figure 2A). Functional potency was confirmed in voltage clamp assays with -80-mV and -100-mV holding membrane potentials in HEK 293 cells heterologously expressing human Ca V 3.1, with IC 50 of 89 and 4,100 nM, respectively (Figure 3).…”

T-Type Calcium Channels Consolidate Tonic Action Potential Output of Thalamic Neurons to Neocortex

“…Using TTA-P2, a potent and specific antagonist of T-type calcium channels (Shipe et al, 2008;Dreyfus et al, 2010), and the dynamic-clamp technique, which allows replaying the same fluctuating conductance sequences (Wolfart et al, 2005;Destexhe and Bal, 2009) during successive experimental conditions, we demonstrate that T-current is a major determinant of singlespike and multispike generation at membrane potentials where T-channels were previously considered to be fully inactivated. A key physiological significance of these results is that the increased recruitment of T-channels with hyperpolarization during tonic firing confers a remarkable robustness to the input-output transfer function of TC neurons across a wide voltage range.…”

“…These data led us to investigate the role of IT in regulating synaptic information transfer in the depolarized state. Using the novel highly specific blocker of T-type channels, TTA-P2 (Shipe et al, 2008;Dreyfus et al, 2010), KO mice lacking the T-channel Ca v 3.1 subunit (Kim et al, 2001) and the dynamicclamp technique, we demonstrate that the activation of T-channels during wake-like states is a major determinant for single and multiple spike occurrence during tonic firing and for the robustness of the thalamocortical transfer of sensory inputs.…”

T-type calcium channels in synaptic plasticity

“…The hypertensive drug mibefradil was also largely used although it inhibits Na C and high-voltage Ca 2C currents as well as voltage-dependent and ATPsensitive K C channels. [21][22][23][24][25][26] Despite these limitations, good indications of a role for T-type channels in longterm synaptic plasticity were nevertheless provided and definite evidence has been recently brought about by the generation of knock-out Cav3 channel mice 27 and the synthesis of the first potent and selective T-type channel antagonists, mainly based on a piperidine chemical structure 28,29 (Table 1). Not surprisingly most evidence was obtained in CNS areas showing a large expression of T-type channels, i.e.…”