New piperidinyl- and 1,2,3,6-tetrahydropyridinyl-pyrimidine derivatives as selective 5-HT1A receptor agonists with highly potent anti-ischemic effects.
A series of new piperidinyl- and 1,2,3,6-tetrahydropyridinyl-pyrimidine derivatives were synthesized. Among these compounds, 4-methyl-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine derivative 23 (SUN N5147) exhibited sub-nanomolar affinity for 5-HT1A receptor with 1000-fold selectivity over both dopamine D2 and alpha1-adrenergic receptors and remarkable neuroprotective activity in a transient middle cerebral artery occlusion (t-MCAO) model.
Kamei
Katsuhide
K
Daiichi Suntory Biomedical Research Co., Ltd, 1-1-1, Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka 618-8513, Japan. Katsuhide_Kamei@dsup.co.jp
Maeda
Noriko
N
Katsuragi-Ogino
Ryoko
R
Koyama
Makoto
M
Nakajima
Mika
M
Tatsuoka
Toshio
T
Ohno
Tomochika
T
Inoue
Teruyoshi
T
D058646:Adrenergic alpha-1 Receptor Agonists; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000188:drug therapy / Q000378:metabolism; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000819:agonists; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D058646:Adrenergic alpha-1 Receptor Agonists; D018696:Neuroprotective Agents; D010879:Piperazines; D011743:Pyrimidines; D017448:Receptors, Dopamine D2; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; C030986:pyrimidine