TY - JOUR
T1 - The discovery and characterization of ML218
T2 - A novel, centrally active T-Type calcium channel inhibitor with robust effects in STN neurons and in a rodent model of Parkinson's disease
AU - Xiang, Zixiu
AU - Thompson, Analisa D.
AU - Brogan, John T.
AU - Schulte, Michael L.
AU - Melancon, Bruce J.
AU - Mi, Debbie
AU - Lewis, L. Michelle
AU - Zou, Bende
AU - Yang, Liya
AU - Morrison, Ryan
AU - Santomango, Tammy
AU - Byers, Frank
AU - Brewer, Katrina
AU - Aldrich, Jonathan S.
AU - Yu, Haibo
AU - Dawson, Eric S.
AU - Li, Min
AU - McManus, Owen
AU - Jones, Carrie K.
AU - Daniels, J. Scott
AU - Hopkins, Corey R.
AU - Xie, Ximin Simon
AU - Conn, P. Jeffrey
AU - Weaver, C. David
AU - Lindsley, Craig W.
PY - 2011/12/21
Y1 - 2011/12/21
N2 - 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.
AB - 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.
KW - Parkinson's disease
KW - T-Type calcium channel
KW - electrophysiology
KW - inhibitor
UR - http://www.scopus.com/inward/record.url?scp=84555194740&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84555194740&partnerID=8YFLogxK
U2 - 10.1021/cn200090z
DO - 10.1021/cn200090z
M3 - Article
C2 - 22368764
AN - SCOPUS:84555194740
SN - 1948-7193
VL - 2
SP - 730
EP - 742
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
IS - 12
ER -