Depression Treatment: A Novel Metabotropic Glutamate Receptor 5 Positive Allosteric Modulator Acts at a Unique Site and Confers Stimulus Bias to mGlu5 Signaling.

A Novel Metabotropic Glutamate Receptor 5 Positive Allosteric Modulator Acts at a Unique Site and Confers Stimulus Bias to mGlu5 Signaling.

Filed under: Depression Treatment

Mol Pharmacol. 2013 Jan 24;
Noetzel MJ, Gregory KJ, Vinson PN, Manka JT, Stauffer SR, Lindsley CW, Niswender CM, Xiang Z, Conn PJ

Metabotropic glutamate receptor 5 (mGlu(5)) is a target for the treatment of central nervous system (CNS) disorders, such as schizophrenia and Alzheimer’s disease. Furthermore, mGlu(5) has been shown to play an important role in hippocampal synaptic plasticity, specifically in long-term depression (LTD) and long-term potentiation (LTP), which is thought to be involved in cognition. Multiple mGlu(5) positive allosteric modulators (PAMs) have been developed from a variety of different scaffolds. Previous work has extensively characterized a common allosteric site on mGlu(5), termed the MPEP binding site. However, one mGlu(5) PAM, CPPHA, interacts with a separate allosteric site on mGlu(5). Using cell-based assays and brain slice preparations, we characterized the interaction of a potent and efficacious mGlu(5) PAM from the CPPHA series termed NCFP. NCFP binds to the “CPPHA site” on mGlu(5) and potentiates mGlu(5)-mediated responses in both recombinant and native systems. However, NCFP provides greater mGlu(5) subtype selectivity than does CPPHA, making it more suitable for studies of effects on mGlu(5) in CNS preparations. Interestingly, NCFP does not potentiate responses involved in hippocampal synaptic plasticity (LTD/LTP), setting it apart from other previously characterized MPEP site PAMs. This suggests that although mGlu(5) PAMs may have similar responses in some systems, they can induce differential effects on mGlu(5)-mediated physiological responses in the CNS. Such stimulus bias by mGlu5 PAMs may complicate drug discovery efforts but would also allow for specifically tailored therapies, if pharmacological biases can be attributed to different therapeutic outcomes.
HubMed – depression

Effects of fluoxetine on cloned Kv4.3 potassium channels.

Filed under: Depression Treatment

Brain Res. 2013 Jan 21;
Jeong I, Choi JS, June SJ

Fluoxetine is widely used for the treatment of depression. We examined the action of fluoxetine on cloned Kv4.3 stably expressed in CHO cells using the whole-cell patch-clamp technique. Fluoxetine did not significantly produce a reduction in the peak amplitude of Kv4.3, but increased the rate of current inactivation in a concentration-dependent manner. Thus, the effect of fluoxetine on Kv4.3 was measured from the integral of the current during the depolarizing pulse. The integral of Kv4.3 was reduced by fluoxetine in a concentration-dependent manner with an IC(50) of 11.8?M. Using first-order kinetics analysis, the apparent association and dissociation rate constants were 1.5µM(-1)s(-1) and 22.2s(-1), respectively, with a K(D) of 14.2µM, similar to the IC(50) value calculated from the concentration-response curve. Under control conditions, the inactivation of Kv4.3 was best fit by a biexponential function. The fast and slow time constants were significantly decreased in the presence of fluoxetine. Time-to-peak and activation kinetics were significantly accelerated by fluoxetine. The block of Kv4.3 by fluoxetine became more prominent as the membrane potential became more depolarized, displaying a shallow voltage dependence (?=0.29) in the full activation voltage range. Fluoxetine did not affect the steady-state inactivation curves, but significantly accelerated the closed- state inactivation of Kv4.3. The block of Kv4.3 by fluoxetine was use-dependent during repetitive stimulation, which explained the slowing of the recovery from inactivation of Kv4.3. Our results indicate that fluoxetine blocks Kv4.3 by preferentially interacting with the open and accelerating closed- state inactivation of the channel.
HubMed – depression

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