title: Identification and synthesis of [1,2,4]triazolo[3,4-a]phthalazine derivatives as high-affinity ligands to the alpha 2 delta-1 subunit of voltage gated calcium channel.
abstract: We have identified and synthesized a series of [1,2,4]triazolo[3,4-a]phthalazine derivatives as high-affinity ligands to alpha 2 delta-1 subunit of voltage gated calcium channels. Structure-activity relationship studies directed toward improving the potency and physical properties of 2 lead to the discovery of 20 (IC(50)=15 nM) and (S)-22 (IC(50)=30 nM). A potent and selective radioligand, [(3)H]-(S)-22 was also synthesized to demonstrate that this ligand binds to the same site as gabapentin.
authors.affiliation: Department of Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA. alec_lebsack@merck.com
authors.forename: Alec D
authors.initials: AD
authors.lastname: Lebsack
authors.forename: Janet
authors.initials: J
authors.lastname: Gunzner
authors.forename: Bowei
authors.initials: B
authors.lastname: Wang
authors.forename: Richard
authors.initials: R
authors.lastname: Pracitto
authors.forename: Hervé
authors.initials: H
authors.lastname: Schaffhauser
authors.forename: Angelina
authors.initials: A
authors.lastname: Santini
authors.forename: Jayashree
authors.initials: J
authors.lastname: Aiyar
authors.forename: Robert
authors.initials: R
authors.lastname: Bezverkov
authors.forename: Benito
authors.initials: B
authors.lastname: Munoz
authors.forename: Wensheng
authors.initials: W
authors.lastname: Liu
authors.forename: Shankar
authors.initials: S
authors.lastname: Venkatraman
mesh_terms: D000588:Amines / Q000378:metabolism; D000700:Analgesics / Q000138:chemical synthesis / Q000494:pharmacology; D001665:Binding Sites; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D003509:Cyclohexanecarboxylic Acids / Q000378:metabolism; D000077206:Gabapentin; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D010793:Phthalazines / Q000138:chemical synthesis / Q000494:pharmacology*; D011869:Radioligand Assay; D013329:Structure-Activity Relationship; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000588:Amines; D000700:Analgesics; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D003509:Cyclohexanecarboxylic Acids; D008024:Ligands; D010793:Phthalazines; C494035:voltage gated calcium channel subunit Ca alpha2delta-1, human; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin