Novel Spiropiperidines as Highly Potent and Subtype Selective σ-Receptor Ligands. Part 1

Abstract

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.

<![CDATA[Binding characteristics of sigma2 receptor ligands]]>

“…Berardi et al, 1998;Berardi et al, 2004;Fujimura et al, 1997;Kawamura et al, 2003;Mach et al, 2004;Maeda et al, 2002;Maier and Wunsch, 2002;Marrazzo et al, 2001;Matsumoto et al, 2004). Of particular interest is a series of substituted tetralins bearing a gem-dimethyl piperidine.…”

Effects of UMB24 and (±)-SM 21, putative σ2-preferring antagonists, on behavioral toxic and stimulant effects of cocaine in mice

“…Although reports of σ 2 ligands abound in the literature (Bertha et al, 1995;Bowen et al, 1995a,b;Kassiou et al, 2005;Mach et al, 1995;Maeda et al, 2002;Maier and Wunsch, 2002;Perregaard et al, 1995;Vangveravong et al, 2006), the primary criterion for these claims appears to be reasonable affinity for this receptor subtype relative to σ 1 , with little consideration for selectivity as compared to non-σ binding sites. In addition, the few σ 2 compounds that have been tested in functional studies appear to act as agonists (Bowen et al, 1995a,b;Crawford et al, 2002;Vilner and Bowen, 2000).…”

An Efficient Synthesis of 1-Thia-5-azaspiro[5.5]undec-2-ene and its Recyclization to 1,5-Diazaspiro[5.5]undec-2-ene and/or Spiro-Thieno[2,3-d]pyrimidin-4(1H)-one Derivatives

“…Scheme 2 outlines the synthesis of 1-thia-5-azaspiro [5.5]undec-2-ene 7 from the cyclocondensation of 2-cyano-3-mercapto-3-phenylamino-acrylamide (1a) with 4-oxo-1-phenyl-cyclohexanecarbonitrile (6) in the presence of catalytic amounts of ptoluenesulfonic acid in boiling ethanol. The structure of compound 7 was determined on the basis of elemental analysis, spectral data and the chemical transformations outlined below.…”

“…These compounds may display pronounced antimicrobial [1], analgesic [2], antiinflammatory [2], antimycobacterial [3], antifungal [4], antitumor [5,6], and antiviral [5,6] activities. Furthermore, 1,3-thiazines are an important type of heterocycles showing also a wide variety of related properties [7 -11].…”