Thiophene Bioisosteres of Spirocyclic σ Receptor Ligands: Relationships between Substitution Pattern and σ Receptor Affinity

Abstract

On the basis of the 6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] framework, a series of more than 30 σ ligands with versatile substituents in 1-, 2'-, and 6'-position has been synthesized and pharmacologically evaluated in order to find novel structure-affinity relationships. It was found that a cyclohexylmethyl residue at the piperidine N-atom instead of a benzyl moiety led to increased σ(2) affinity and therefore to decreased σ(1)/σ(2) selectivity. Small substituents (e.g., OH, OCH(3), CN, CH(2)OH) in 6'-position adjacent to the O-atom were well tolerated by the σ(1) receptor. Removal of the substituent in 6'-position resulted in very potent but unselective σ ligands (13). A broad range of substituents with various lipophilic and H-bond forming properties was introduced in 2'-position adjacent to the S-atom without loss of σ(1) affinity. However, very polar and basic substituents in both 2'- and 6'-position decreased the σ(1) affinity considerably. It is postulated that the electron density of the thiophene moiety has a big impact on the σ(1) affinity.

Investigational sigma-1 receptor antagonists for the treatment of pain

“…Compound 7, with moderate/poor selectivity over the s 2 R but high selectivity against more than other 60 other molecular targets in vitro, showed high in vivo analgesic (antiallodynic) efficacy and potency in the capsaicin test in mice [61]. Several spirocyclic derivatives were subsequently described (8 --10) with very good affinity for the s 1 R and excellent selectivity (over more than 60 other receptors, ion channels and neurotransmitter transporter as described for some of them), and active (antiallodynic) in the capsaicin test, although their in vivo potency was moderate and inferior compared to that of 7 [62][63][64][65][66].…”

Pharmacophore Models and Development of Spirocyclic Ligands for σ1 Receptors

“…(11) [33]. The extraordinarily high 1 affinity of 13 stimulated the design of regioisomeric spirocyclic thiophene 16, which is also a very potent 1 ligand (K i = 0.22 nM) [34] Fig.…”

Structure–Activity Relationships within a Series of σ1 and σ2 Receptor Ligands: Identification of a σ2 Receptor Agonist (BS148) with Selective Toxicity against Metastatic Melanoma

“…We recently reported a new series of conformationally restricted spirodioxolane, among which 1 a and 1 b showed high affinity and good selectivity for σ 1 R, behaving as σ 1 R agonists (Figure ) . The spirocyclic substructure has been shown to be an interesting moiety for σR ligands …”