Conversion of a highly selective sigma-1 receptor-ligand to sigma-2 receptor preferring ligands with anticocaine activity.
Cocaine's toxicity can be mitigated by blocking its interaction with sigma-1 receptors. The involvement of sigma-2 receptors remains unclear. To investigate their potential role, we have designed compounds through a convergent synthesis utilizing a highly selective sigma-1 ligand and elements of a selective sigma-2 ligand. Among the synthesized compounds was produced a subnanomolar sigma-2 ligand with an 11-fold preference over sigma-1 receptors. These compounds may be useful in developing effective pharmacotherapies for cocaine toxicity.
Mésangeau
Christophe
C
Department of Medicinal Chemistry, The University of Mississippi, Mississippi 38677, USA.
Narayanan
Sanju
S
Green
Andrea M
AM
Shaikh
Jamaluddin
J
Kaushal
Nidhi
N
Viard
Eddy
E
Xu
Yan-Tong
YT
Fishback
James A
JA
Poupaert
Jacques H
JH
Matsumoto
Rae R
RR
McCurdy
Christopher R
CR
D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D003042:Cocaine / Q000633:toxicity*; D019970:Cocaine-Related Disorders / Q000188:drug therapy; D066298:In Vitro Techniques; D008024:Ligands; D051379:Mice; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000097605:Sigma-1 Receptor
D000927:Anticonvulsants; D003042:Cocaine; D008024:Ligands; D010080:Oxazoles; D010879:Piperazines; D017480:Receptors, sigma; D013844:Thiazoles; D000097605:Sigma-1 Receptor; C106107:sigma-2 receptor