The discovery and characterization of ML218: A novel, centrally active T-Type calcium channel inhibitor with robust effects in STN neurons and in a rodent model of Parkinson's disease

Zixiu Xiang, Analisa D. Thompson, John T. Brogan, Michael L. Schulte, Bruce J. Melancon, Debbie Mi, L. Michelle Lewis, Bende Zou, Liya Yang, Ryan Morrison, Tammy Santomango, Frank Byers, Katrina Brewer, Jonathan S. Aldrich, Haibo Yu, Eric S. Dawson, Min Li, Owen McManus, Carrie K. Jones, J. Scott DanielsCorey R. Hopkins, Ximin Simon Xie, P. Jeffrey Conn, C. David Weaver, Craig W. Lindsley

Research output: Contribution to journalArticle

Abstract

T-Type Ca 2+ channel inhibitors hold tremendous therapeutic potential for the treatment of pain, epilepsy, sleep disorders, essential tremor, and other neurological disorders; however, a lack of truly selective tools has hindered basic research, and selective tools from the pharmaceutical industry are potentially burdened with intellectual property (IP) constraints. Thus, an MLPCN high-throughput screen (HTS) was conducted to identify novel T-type Ca 2+ channel inhibitors free from IP constraints, and freely available through the MLPCN, for use by the biomedical community to study T-type Ca 2+ channels. While the HTS provided numerous hits, these compounds could not be optimized to the required level of potency to be appropriate tool compounds. Therefore, a scaffold hopping approach, guided by SurflexSim, ultimately afforded ML218 (CID 45115620), a selective T-type Ca 2+ (Ca v3.1, Ca v3.2, Ca v3.3) inhibitor (Ca v3.2, IC 50 = 150 nM in Ca 2+ flux; Ca v3.2 IC 50 = 310 nM; and Ca v3.3 IC 50 = 270 nM, respectively in patch clamp electrophysiology) with good DMPK properties, acceptable in vivo rat PK, and excellent brain levels. Electrophysiology studies in subthalamic nucleus (STN) neurons demonstrated robust effects of ML218 on the inhibition of T-type calcium current, inhibition of low threshold spike, and rebound burst activity. Based on the basal ganglia circuitry in Parkinson’s disease (PD), the effects of ML218 in STN neurons suggest a therapeutic role for T-type Ca 2+ channel inhibitors, and ML218 was found to be orally efficacious in haloperidol-induced catalepsy, a preclinical PD model, with comparable efficacy to an A 2A antagonist, a clinically validated PD target. ML218 proves to be a powerful new probe to study T-type Ca 2+ function in vitro and in vivo, and freely available.

Original languageEnglish (US)
Pages (from-to)730-742
Number of pages13
JournalACS Chemical Neuroscience
Volume2
Issue number12
DOIs
StatePublished - Dec 21 2011

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Keywords

  • electrophysiology
  • inhibitor
  • Parkinson's disease
  • T-Type calcium channel

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Physiology
  • Cognitive Neuroscience

Cite this

Xiang, Z., Thompson, A. D., Brogan, J. T., Schulte, M. L., Melancon, B. J., Mi, D., Lewis, L. M., Zou, B., Yang, L., Morrison, R., Santomango, T., Byers, F., Brewer, K., Aldrich, J. S., Yu, H., Dawson, E. S., Li, M., McManus, O., Jones, C. K., ... Lindsley, C. W. (2011). The discovery and characterization of ML218: A novel, centrally active T-Type calcium channel inhibitor with robust effects in STN neurons and in a rodent model of Parkinson's disease. ACS Chemical Neuroscience, 2(12), 730-742. https://doi.org/10.1021/cn200090z