Pharmacological and Pharmacokinetic Studies of a K_Ca2.2 Positive Allosteric Modulator

<p>Small-conductance Ca²⁺-activated potassium channels (K_Ca2.x) family is widely expressed in neurons, the heart, and endothelial cells. K_Ca2.x channels are named small conductance Ca²⁺-activated potassium channels due to their comparatively low single-channel conductance and are activated solely by rises in intracellular Ca²⁺. The family has three subtypes: K_Ca2.1, K_Ca2.2, and K_Ca2.3, encoded by <em>KCNN1</em>, <em>KCNN2</em>, and <em>KCNN3</em> genes, respectively. K_Ca2.x channels regulate neuronal excitability and responsiveness to synaptic input patterns. Small-conductance Ca²⁺-activated potassium channels subtype 2 (K_Ca2.2, also called SK2) is a promising drug target for spinocerebellar ataxias (SCAs), genetic disorders with no available treatment. Heterozygous genetic mutations of K_Ca2.2 channels have been associated with autosomal dominant neurodevelopmental disorders, including cerebellar ataxia and tremor in humans and rodents. The structure-function studies of the rat K_Ca2.2 channel using seven pathogenic mutations (I289N, I360M, Y362C, G363S, I389V, L174P, and L433P) associated with these disorders were performed to investigate the insight of these disorders related to K_Ca2.2. The dominant mutations negatively suppressed and completely abolished the activity of the co-expressed K_Ca2.2_WT channel, suggesting that these mutations may be causative in neurodevelopmental disorders. Additionally, the co-expression of the K_Ca2.2_I289N and the K_Ca2.2_WT channels reduced the apparent Ca²⁺ sensitivity compared with the K_Ca2.2_WT channel rescued by a K_Ca2.2 positive modulator. A positive allosteric modulator of K_Ca2.2/K_Ca2.3 channels (compound <strong>2q</strong>) has been developed, and a method for quantitating it in mouse plasma has been validated using FDA guidelines. The developed assay is suitable for preclinical pharmacokinetic-pharmacodynamic studies of <strong>2q</strong> as a potential drug candidate for ataxias.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Pharmaceutical Sciences

Year dc:date.available

2023

Author dc:creator

• Rahman, Mohammad Asikur

Contributors dc:contributor

• Dr. Miao Zhang
• Dr. Sun Yang
• Dr. Keykavous Parang
• Dr. Meng Cui

• KCa2.2
• Spinocerebellar Ataxia
• Mutagenesis Study
• 2q
• Positive modulator
• LC-MS method development & validation
• Biophysics
• Molecular Biology
• Pharmacology

Repository record dc:identifier

https://digitalcommons.chapman.edu/pharmaceutical_sciences_dissertations/30

OAI identifier oai:identifier

oai:digitalcommons.chapman.edu:pharmaceutical_sciences_dissertations-1031