Loratadine analogues as MAGL inhibitors.
Compound 12a (JZP-361) acted as a potent and reversible inhibitor of human recombinant MAGL (hMAGL, IC50=46 nM), and was found to have almost 150-fold higher selectivity over human recombinant fatty acid amide hydrolase (hFAAH, IC50=7.24 μM) and 35-fold higher selectivity over human α/β-hydrolase-6 (hABHD6, IC50=1.79 μM). Additionally, compound 12a retained H1 antagonistic affinity (pA2=6.81) but did not show cannabinoid receptor activity, when tested at concentrations ⩽ 10 μM. Hence, compound 12a represents a novel dual-acting pharmacological tool possessing both MAGL-inhibitory and antihistaminergic activities.
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland. Electronic address: jayendra.patel@uef.fi.
Jayendra Z
JZ
Patel
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
Stephen
S
Ahenkorah
School of Medicine, Institute of Biomedicine/Physiology, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
Miia
M
Vaara
Department of Synthesis and Technology of Drugs, Faculty of Pharmacy, Medical University of Lodz, 90-151 Lodz, Poland.
Marek
M
Staszewski
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
Yahaya
Y
Adams
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
Tuomo
T
Laitinen
School of Medicine, Institute of Biomedicine/Physiology, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
Dina
D
Navia-Paldanius
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
Teija
T
Parkkari
School of Medicine, Institute of Biomedicine/Physiology, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
Juha R
JR
Savinainen
Department of Synthesis and Technology of Drugs, Faculty of Pharmacy, Medical University of Lodz, 90-151 Lodz, Poland.
Krzysztof
K
Walczyński
School of Medicine, Institute of Biomedicine/Physiology, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
Jarmo T
JT
Laitinen
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
Tapio J
TJ
Nevalainen
D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D017336:Loratadine / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D004791:Enzyme Inhibitors; D017336:Loratadine; D008994:Monoacylglycerol Lipases; D011994:Recombinant Proteins; D000099252:Fatty Acid Amide Hydrolases
2-Arachidonoyl glycerol; Fatty acid amide hydrolase; Loratadine; Monoacylglycerol lipase; α/β hydrolase-6