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

Alec D Lebsack; Janet Gunzner; Bowei Wang; Richard Pracitto; Hervé Schaffhauser; Angelina Santini; Jayashree Aiyar; Robert Bezverkov; Benito Munoz; Wensheng Liu; Shankar Venkatraman

doi:10.1016/j.bmcl.2004.03.008

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

Bioorg Med Chem Lett. 2004 May 17;14(10):2463-7. doi: 10.1016/j.bmcl.2004.03.008.

Authors

Alec D Lebsack¹, Janet Gunzner, Bowei Wang, Richard Pracitto, Hervé Schaffhauser, Angelina Santini, Jayashree Aiyar, Robert Bezverkov, Benito Munoz, Wensheng Liu, Shankar Venkatraman

Affiliation

¹ Department of Chemistry, Merck Research Laboratories, MRLSDB2, 3535 General Atomics Court, San Diego, CA 92121, USA. [email protected]

PMID: 15109633
DOI: 10.1016/j.bmcl.2004.03.008

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.

MeSH terms

Amines / metabolism
Analgesics / chemical synthesis
Analgesics / pharmacology
Binding Sites
Calcium Channel Blockers / chemical synthesis*
Calcium Channel Blockers / pharmacology
Calcium Channels / metabolism*
Cyclohexanecarboxylic Acids / metabolism
Gabapentin
Humans
Inhibitory Concentration 50
Ligands
Phthalazines / chemical synthesis
Phthalazines / pharmacology*
Radioligand Assay
Structure-Activity Relationship
gamma-Aminobutyric Acid / metabolism

Substances

Amines
Analgesics
Calcium Channel Blockers
Calcium Channels
Cyclohexanecarboxylic Acids
Ligands
Phthalazines
voltage gated calcium channel subunit Ca alpha2delta-1, human
gamma-Aminobutyric Acid
Gabapentin