ML335

Cat No:	I013986
Cas No:	825658-06-8
Product-Name:	ML335
IUPAC Name:	N-[(2,4-dichlorophenyl)methyl]-4-(methanesulfonamido)benzamide
InChI:	InChI=1S/C15H14Cl2N2O3S/c1-23(21,22)19-13-6-3-10(4-7-13)15(20)18-9-11-2-5-12(16)8-14(11)17/h2-8,19H,9H2,1H3,(H,18,20)
InChIKey:	RDFIQTZRJRVFHK-UHFFFAOYSA-N
SMILES:	CS(=O)(=O)NC1=CC=C(C=C1)C(=O)NCC2=C(C=C(C=C2)Cl)Cl

ML335(cas 825658-06-8) is a potent and selective TREK-1/2 Activator. ML335 is an agonist for OPRM1-OPRD1 heterdimerization with an EC50 of 403 nM, and selectivities vs. OPRM1, OPRD1, and HTR5A of 37, 2.7, and >99, respectively.

1. Nature. 2017 Jul 20;547(7663):364-368. doi: 10.1038/nature22988. Epub 2017 Jul 10.
K2P2.1 (TREK-1)-activator complexes reveal a cryptic selectivity filter binding site.
Lolicato M(1), Arrigoni C(1), Mori T(2), Sekioka Y(2), Bryant C(3), Clark KA(1), Minor DL Jr(1)(4)(5)(6)(7).
Author information:
(1)Cardiovascular Research Institute, University of California, San Francisco, California 941158-9001, USA. (2)Ono Pharmaceutical Co. Ltd, Mishima-Gun, Osaka 618-8585, Japan. (3)Small Molecule Discovery Center, University of California, San Francisco, California 93858-2330, USA. (4)Departments of Biochemistry and Biophysics, and Cellular and Molecular Pharmacology, University of California, San Francisco, California 941158-9001, USA. (5)California Institute for Quantitative Biomedical Research, University of California, San Francisco, California 941158-9001, USA. (6)Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, California 941158-9001, USA. (7)Molecular Biophysics and Integrated Bio-imaging Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
Polymodal thermo- and mechanosensitive two-pore domain potassium (K2P) channels of the TREK subfamily generate 'leak' currents that regulate neuronal excitability, respond to lipids, temperature and mechanical stretch, and influence pain, temperature perception and anaesthetic responses. These dimeric voltage-gated ion channel (VGIC) superfamily members have a unique topology comprising two pore-forming regions per subunit. In contrast to other potassium channels, K2P channels use a selectivity filter 'C-type' gate as the principal gating site. Despite recent advances, poor pharmacological profiles of K2P channels limit mechanistic and biological studies. Here we describe a class of small-molecule TREK activators that directly stimulate the C-type gate by acting as molecular wedges that restrict interdomain interface movement behind the selectivity filter. Structures of K2P2.1 (also known as TREK-1) alone and with two selective K2P2.1 (TREK-1) and K2P10.1 (TREK-2) activators-an N-aryl-sulfonamide, ML335, and a thiophene-carboxamide, ML402-define a cryptic binding pocket unlike other ion channel small-molecule binding sites and, together with functional studies, identify a cation-π interaction that controls selectivity. Together, our data reveal a druggable K2P site that stabilizes the C-type gate 'leak mode' and provide direct evidence for K2P selectivity filter gating.

2. Characterization of an agonist probe for opioid receptor mu 1 (OPRM1)-opioid receptor delta 1 (OPRD1) heterodimerization.
Pinello C(1), Guerrero M(2), Eberhart C(1), Volmar CH(1), Saldanha SA(1), Cayanan C(2), Urbano M(2), Brown SJ(2), Ferguson J(2), Gomes I(3), Devi LA(3), Roberts E(2), Hodder P(1), Rosen H(2). In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. 2012 Dec 17.
Author information:
(1) The Scripps Research Institute, Jupiter, FL (2) The Scripps Research Institute, La Jolla, CA (3) Mount Sinai School of Medicine.
Opiates such as morphine are the choice analgesic in the treatment of chronic pain due to their potent and rapid action. Opioid receptors belong to the family of G protein-coupled receptors (GPCRs), one of the largest gene families in the mammalian genome. The OPRM1 gene encodes the mu opioid receptor, which is the primary site of action for morphine and other commonly used opioids such as heroin, fentanyl, and methadone. The long-term use of opiates is limited because of the development of tolerance and dependence, as well as respiratory suppression and constipation. Due to their clinical importance, various strategies have been considered for making opiates more effective while curbing liabilities such as addiction. One such strategy has been to use a combination of drugs to improve the effectiveness of morphine. In particular, delta opioid receptor (OPRD1) ligands have been useful in enhancing morphine’s potency, but the underlying molecular basis is not understood. It has been shown that modulation of receptor function by physical association between OPRM1 and OPRD1 is a potential mechanism; heteromerization of OPRM1 with OPRD1 leads to the modulation of receptor binding and signaling properties. It has further been shown that the selective activation of the OPRM1-OPRD1 heteromer by a combination of OPRM1 agonist with OPRD1 antagonist can be blocked by antibodies that selectively recognize the heteromer. Therefore, the identification of compounds that selectively activate OPRM1-OPRD1 heterodimerization may have potential in the treatment of pain and alleviate unwanted effects associated with opiate use. The Scripps Research Institute Molecular Screening Center (SRIMSC), part of the Molecular Libraries Probe Production Centers Network (MLPCN), reports here an agonist for OPRM1-OPRD1 heterdimerization, ML335, with an EC50 of 403 nM, and selectivities vs. OPRM1, OPRD1, and HTR5A of 37, 2.7, and >99, respectively.