Introduction

The Sedation is the most common adverse drug reaction (ADR) for CNS drug. This sedation off target Portfolio is designed to identify ion channels and GPCRs associated with sedative side effects, helping to minimize undesired central nervous system (CNS) depression during drug development. This panel includes targets that regulate neuronal excitability, synaptic transmission, and neurotransmitter release, all of which contribute to sedation as an off-target effect.

Key Targets in the Portfolio:

    1. Ion Channels:

    √ GABA Receptors (GABAα1β2γ2，GABAα1β3γ2): Overactivation of GABAergic transmission can lead to excessive CNS inhibition, causing sedation.

    √ Potassium Channels (KCNQ2/3, BK, IK): Hyperpolarization caused by potassium channel activation can suppress neuronal activity, contributing to sedation.

    √ Voltage-Gated Calcium Channels (Cav1.3, Cav2.1, Cav2.2): These channels regulate neurotransmitter release; inhibition may dampen synaptic activity, leading to sedative effects.

    √ Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels (HCN1, HCN2): Reduced activity of these channels can suppress wakefulness, promoting sedation.

    2. GPCRs (G Protein-Coupled Receptors):

    √ Histamine H1 Receptors: Blockade of H1 receptors is a well-known cause of sedation, commonly seen in antihistamines.

    √ 5-HT1A and 5-HT2 Receptors (Serotonin): Modulation of serotonergic signaling can influence arousal and sleep-wake cycles.

    √ Dopamine D2 Receptors: Inhibition can suppress dopamine signaling, reducing alertness and inducing sedation.

    √ Adrenergic α2 Receptors: Activation can dampen CNS arousal pathways, contributing to sedative effects.

    √ Muscarinic Acetylcholine Receptors (M1, M2): Antagonism of these receptors can reduce arousal, resulting in sedation.

Sedation off target Portfolio

The Sedation Off-Targets Portfolio provides a comprehensive framework for screening ion channels and GPCRs implicated in sedative side effects. By identifying and mitigating these off-target interactions, the panel supports the creation of safer and more targeted therapeutic