title: Synthesis and biological evaluation of new 4-arylpiperidines and 4-aryl-4-piperidinols: dual Na(+) and Ca(2+) channel blockers with reduced affinity for dopamine D(2) receptors.
abstract: A series of novel 4-arylpiperidines and 4-aryl-4-piperidinols (2a-f, 3a-f and 4a-f) was synthesized and evaluated for blocking effects on both neuronal Na(+) and T-type Ca(2+) channels and binding affinity for dopamine D(2) receptors. Most of the compounds blockaded both ion channels with potency greater than or equal to flunarizine 1a which was adopted as a reference standard. In addition, these compounds had significantly reduced affinity for dopamine D(2) receptors which is common in this class of structure. Compounds 2a-f, 3a-f and 4a-f exhibited potent anticonvulsant effects following systemic (ip) administration on audiogenic seizures in DBA/2 mice, indicating their excellent brain permeability. The neuroprotective activity of 2a, 3a and 4a was also assessed in a transient middle cerebral artery occlusion (MCAO) model. These compounds significantly reduced neuronal damage without affecting ischemic hyperthemia, while flunarizine 1a produced only minor reductions. In particular, 4a had 1.7-fold the potency in this MCAO model but only 1/20 the affinity for dopamine D(2) receptors of 1a. The superposition of 2a, 3a and 4a on the basis of analyses of systematic conformation and similar structure has revealed that the cinnamyl, phenacyl and phenoxypropanol groups are likely to be structurally and biologically equivalent. Moreover, the superposition of 2a and 2f shows that diphenyl ether and biphenyl groups occupy a similar space, suggesting that both groups act as a bioisostere for the blockade of ion channels; however, this is not the case for dopamine D(2) receptors since only biphenyl compounds such as 2f had high affinity similar to flunarizine 1a. Compound 4a (SUN N5030) has a good pharmacological profile and may be useful in the alleviation and treatment of ischemic diseases.
authors.affiliation: Suntory Biomedical Research Limited, 1-1-1, Wakayamadai, Shimamoto-cho, Mishima-gun, 618-8503, Osaka, Japan. hirokazu_annoura@suntory.co.jp
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Annoura
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nakanishi
authors.forename: Mayumi
authors.initials: M
authors.lastname: Uesugi
authors.forename: Atsuko
authors.initials: A
authors.lastname: Fukunaga
authors.forename: Seiichi
authors.initials: S
authors.lastname: Imajo
authors.forename: Atsuko
authors.initials: A
authors.lastname: Miyajima
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Tamura-Horikawa
authors.forename: Shigeki
authors.initials: S
authors.lastname: Tamura
mesh_terms: D000818:Animals; D001671:Biochemistry / Q000379:methods; D002121:Calcium Channel Blockers / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005260:Female; D005444:Flunarizine / Q000737:chemistry / Q000494:pharmacology; D007511:Ischemia / Q000188:drug therapy; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018696:Neuroprotective Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010647:Phenyl Ethers / Q000737:chemistry* / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism*; D012640:Seizures / Q000188:drug therapy; D026941:Sodium Channel Blockers / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D002121:Calcium Channel Blockers; D018696:Neuroprotective Agents; D010647:Phenyl Ethers; D010880:Piperidines; D017448:Receptors, Dopamine D2; C401940:SUN N5030; D026941:Sodium Channel Blockers; D005444:Flunarizine