Synthesis and biological evaluation of new 4-arylpiperidines and 4-aryl-4-piperidinols:: Dual Na+ and Ca2+ channel blockers with reduced affinity for dopamine D2 receptors

A series of novel 4-arylpiperidines and 4-aryl-4-piperidinols (2a-f, 3a f and 4a-f) wits synthesized and evaluated for blocking effects on both neuronal Na+ and T-type Ca2+ channels and binding affinity for dopamine D-2 receptors. Most or the compounds blockaded both ion channels with potency greater than or equal to flunarizine Ia 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 Ia 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 phenoxy-propanol 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 Ia. Compound 4a (SUN N5030) has a good pharmacological profile and may be Useful in the alleviation and treatment or ischemic diseases. (C) 2001 Elsevier Science Ltd. All rights reserved.