TY - JOUR
T1 - Aminopyrimidines with high affinity for both serotonin and dopamine receptors
AU - Wustrow, David
AU - Belliotti, Thomas
AU - Glase, Shelly
AU - Kesten, Suzanne Ross
AU - Johnson, Don
AU - Colbry, Norman
AU - Rubin, Ronald
AU - Blackburn, Anthony
AU - Akunne, Hyacinth
AU - Corbin, Ann
AU - Duff Davis, M.
AU - Georgic, Lynn
AU - Whetzel, Steven
AU - Zoski, Kim
AU - Heffner, Thomas
AU - Pugsley, Thomas
AU - Wise, Lawrence
PY - 1998/2/26
Y1 - 1998/2/26
N2 - A series of {4-[2-(4-arylpiperazin-1-yl)alkyl]cyclohexyl}pyrimidin-2- ylamines was prepared and found to have receptor binding affinity for D2 and D3 dopamine (DA) receptors and serotonin 5-HT1A receptors. The structural contributions to D2/D3 and 5-HT1A receptor binding of the aminopyrimidine, cycloalkyl, and phenylpiperazine portions of the molecule were examined. From these studies compounds 14, 39, 42, 43, having potent affinity for both DA D2 and 5-HT1A receptors, were evaluated for intrinsic activity at these receptors, in vitro and in vivo. Compound 14 (PD 158771) had a profile indicative of partial agonist activity at both D2 and 5-HT1A receptors causing partially decreased synthesis of the neurotransmitters DA and 5-HT and their metabolites. This compound has a profile in behavioral tests that is predictive of antipsychotic activity, suggesting that mixed partial agonists such as 14 may have utility as antipsychotic agents with increased efficacy and decreased side effects.
AB - A series of {4-[2-(4-arylpiperazin-1-yl)alkyl]cyclohexyl}pyrimidin-2- ylamines was prepared and found to have receptor binding affinity for D2 and D3 dopamine (DA) receptors and serotonin 5-HT1A receptors. The structural contributions to D2/D3 and 5-HT1A receptor binding of the aminopyrimidine, cycloalkyl, and phenylpiperazine portions of the molecule were examined. From these studies compounds 14, 39, 42, 43, having potent affinity for both DA D2 and 5-HT1A receptors, were evaluated for intrinsic activity at these receptors, in vitro and in vivo. Compound 14 (PD 158771) had a profile indicative of partial agonist activity at both D2 and 5-HT1A receptors causing partially decreased synthesis of the neurotransmitters DA and 5-HT and their metabolites. This compound has a profile in behavioral tests that is predictive of antipsychotic activity, suggesting that mixed partial agonists such as 14 may have utility as antipsychotic agents with increased efficacy and decreased side effects.
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U2 - 10.1021/jm9707378
DO - 10.1021/jm9707378
M3 - Article
C2 - 9513604
AN - SCOPUS:15144361740
VL - 41
SP - 760
EP - 771
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 5
ER -