Synthesis of spiro[isobenzofuran-1(3H),4'-piperidines] as potential central nervous system agents. 5. Conformationally mobile analogues derived by furan ring opening.
Synthesis and antitetrabenazine activity of 4-[2-(arylmethyl)phenyl]piperidines and 4-(benzyloxy)-4-phenylpiperidines, prepared as simplified and possibly more readily synthesized analogues of 3-phenylspiro[isobenzofuran-1 (3H),4'-piperidine], are reported. Several 4-[2-(arylmethyl)phenyl]piperidines display antitetrabenazine activity comparable to imipramine or amitriptyline but are two- to fourfold less active than analogous 3-arylspiro[isobenzofuran-1(3H),4'-piperidines]. Structure--activity relationships for 4-[2p(arylmethyl)phenyl]piperidines are generally similar to the profile established for 3-arylspiro[isobenzofuran-1(3H),4'-piperidines]. Significant antitetrabenazine activity is associated only with derivatives where the arylmethyl group is ortho to the piperidine ring. 4-(Benzyloxy)-4-phenylpiperidines and 4-[2-(arylmethyl)phenyl]-4-piperidinols and the corresponding methyl ethers and esters display weak to modest antitetrabenazine activity. 4-[2-(Arylmethyl)phenyl]-1,2,3,6-tetrahydropyridine derivatives, at best, exhibit modest antitetrabenazine activity, with the exception of 4-[2-(phenylmethyl)phenyl]-1,2,3,6-tetrahydropyridine which is approximately equipotent with amitriptyline. The results of these investigations allow certain speculations to be made with respect to the role of the furan ring in the 3-arylspiro[isobenzofuran-1(3H),4'-piperidines] and antitetrabenazine activity.
D000818:Animals; D000928:Antidepressive Agents / Q000138:chemical synthesis*; D001572:Benzofurans / Q000138:chemical synthesis / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D051379:Mice; D009638:Norepinephrine / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013747:Tetrabenazine / Q000037:antagonists & inhibitors
D000928:Antidepressive Agents; D001572:Benzofurans; D010880:Piperidines; D013141:Spiro Compounds; D009638:Norepinephrine; D013747:Tetrabenazine