Analogues of the potential antipsychotic agent 1192U90: amide modifications.
Analogues of 2-amino-N-(4-(4-(1,2-benzisothiazol-3-yl)-l-piperazinyl) -butyl)benzamide hydrochloride (1192U90) were prepared and evaluated in receptor binding assays for the dopamine D2, serotonin 5-HT1a, and serotonin 5-HT2 receptors. Eight compounds have been synthesized in which the amide group of 1192U90 has been replaced with a variety of functional groups (i.e. ester, ketone, thioamide, butyramide, butyranilide, sulfonamide, alkoxyamide and hydrazide). These compounds exhibited moderate to potent affinities (0.55-200 nM) for all three receptors. Several analogues exhibited improved selectivity for the 5-HT2 receptor with D2/5-HT2 binding ratios greater than 1192U90.
Navas
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F
Division of Chemistry, Glaxo Wellcome Inc., North Carolina 27709, USA.
Tang
F L
FL
Schaller
L T
LT
Norman
M H
MH
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D010879:Piperazines; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013844:Thiazoles; C098658:1192U90