Novel spiropiperidines as highly potent and subtype selective sigma-receptor ligands. Part 1.
A series of spiro[[2]benzopyran-1,4'-piperidines] and spiro[[2]benzofuran-1,4'-piperidines] of general structure 10 is prepared, and the affinity for sigma(1)- and sigma(2)-receptors is investigated by means of radioligand binding assays. The synthesis of the spiropiperidines 14a and 23 proceeds from bromine/lithium exchange of the bromoacetals 11 and 21, addition to piperidin-4-one 12a, and subsequent cyclization. Systematic variations of the substituent R at the nitrogen atom, the group X in position 3, and the ring size of the oxygen heterocycle are performed. The sigma(1)- and sigma(2)-receptor affinities are determined with guinea pig brain and rat liver membrane preparations using [(3)H]-labeled (+)-pentazocine and ditolylguanidine, respectively. Test results show that a benzyl residue at the piperidine nitrogen atom and a methoxy group in position 3 are advantageous for high sigma(1)-receptor affinity. In this series the 1'-benzyl-3-methoxy-3,4-dihydrospiro[[2]benzopyran-1,4'-piperidine] (14a) and the 1'-benzyl-3-methoxy-3H-spiro[[2]benzofuran-1,4'-piperidine] (23) are among the most potent sigma(1)-ligands interacting in the low nanomolar range with sigma(1)-receptors (14a, K(i) = 1.29 nM; 23, K(i) = 1.14 nM). Variation of the nitrogen substituent R from benzyl to H, alkyl, phenyl, or omega-phenylalkyl and the group X from methoxy to hydroxy, carbonyl, or alkyloxy led to reduced sigma(1)-receptor affinity. In addition to their high sigma(1)-receptor affinity, the spiropiperidines 14a and 23 display excellent selectivity toward sigma(2)-receptors (sigma(1)/sigma(2) = 2708 and 1130) and several other receptor and reuptake systems. Introduction of a polar hydroxy group in position 3 and elongation of the distance between the piperidine nitrogen atom and the phenyl moiety result in ligands with considerable sigma(2)-receptor affinity and therefore diminished sigma(1)/sigma(2)-receptor selectivity. The hemiacetalic 1'-(3-phenylpropyl)-3,4-dihydrospiro[[2]benzopyran-1,4'-piperidin]-3-ol (15e) represents the most active sigma(2)-receptor ligand in this series with a K(i) value of 83.1 nM.
Maier
Christoph A
CA
Pharmazeutisches Institut der Universität Freiburg, Albertstrasse 25, 79104 Freiburg i. Br., Germany.
Wünsch
Bernhard
B
D000080:Acetals / Q000737:chemistry; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008024:Ligands; D008099:Liver / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017480:Receptors, sigma / Q000378:metabolism*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000097605:Sigma-1 Receptor
D000080:Acetals; D008024:Ligands; D010880:Piperidines; D011753:Pyrones; D017480:Receptors, sigma; D013141:Spiro Compounds; D000097605:Sigma-1 Receptor; C446057:1'-(3-phenylpropyl)-3,4-dihydrospiro((2)benzopyran-1,4'-piperidin)-3-ol; C106107:sigma-2 receptor