Maier Christoph A, Wünsch Bernhard
Pharmazeutisches Institut der Universität Freiburg, Albertstrasse 25, 79104 Freiburg i. Br., Germany.
J Med Chem. 2002 Jan 17;45(2):438-48. doi: 10.1021/jm010992z.
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.
制备了一系列具有通式10的螺[[2]苯并吡喃-1,4'-哌啶]和螺[[2]苯并呋喃-1,4'-哌啶]，并通过放射性配体结合试验研究了它们对σ(1)和σ(2)受体的亲和力。螺哌啶14a和23的合成是从溴代缩醛11和21的溴/锂交换、与哌啶-4-酮12a加成以及随后的环化反应开始的。对氮原子上的取代基R、3位的基团X以及氧杂环的环大小进行了系统变化。分别使用[³H]标记的(+)-喷他佐辛和二对甲苯基胍，在豚鼠脑和大鼠肝膜制剂中测定σ(1)和σ(2)受体亲和力。测试结果表明，哌啶氮原子上的苄基残基和3位的甲氧基有利于高σ(1)受体亲和力。在该系列中，1'-苄基-3-甲氧基-3,4-二氢螺[2]苯并吡喃-1,4'-哌啶和1'-苄基-3-甲氧基-3H-螺[2]苯并呋喃-1,4'-哌啶是在低纳摩尔范围内与σ(1)受体相互作用的最有效σ(1)配体之一(14a，K(i)=1.29 nM；23，K(i)=1.14 nM)。氮取代基R从苄基变为H、烷基、苯基或ω-苯烷基，以及基团X从甲氧基变为羟基、羰基或烷氧基，导致σ(1)受体亲和力降低。除了具有高σ(1)受体亲和力外，螺哌啶14a和23对σ(2)受体表现出优异的选择性(σ(1)/σ(2)=2708和1130)以及对其他几种受体和再摄取系统也有选择性。在3位引入极性羟基并延长哌啶氮原子与苯基部分之间的距离，会产生具有相当σ(2)受体亲和力的配体，因此σ(1)/σ(2)受体选择性降低。半缩醛1'-(3-苯丙基)-3,4-二氢螺[[2]苯并吡喃-1,4'-哌啶]-3-醇(15e)是该系列中最具活性的σ(2)受体配体，K(i)值为83.1 nM。
