3-Amino-3,4-dihydro-2H-1-benzopyran Derivatives as 5-HT_1A Receptor Ligands and Potential Anxiolytic Agents. 2. Synthesis and Quantitative Structure−Activity Relationship Studies of Spiro[pyrrolidine- and piperidine-2,3‘(2‘H)-benzopyrans]

Abstract

In continuation of our work on 3-amino-3,4-dihydro-2H-1-benzopyran derivatives with high affinity for 5-HT1A receptors, we have prepared rigid spirobenzopyran analogues designed from the pharmacophore models of Mellin and selected via a quantitative structure-activity relationship approach mainly based on similarity indices. A series of spiro[pyrrolidine- and piperidine-2,3'(2'H)-benzopyrans] with various substitutions on the aromatic ring as well as on the extracyclic spiranic nitrogen atom were then synthesized and evaluated for their serotonergic and dopaminergic activities. Good correlation between the predicted and the experimental binding values was observed with an average difference of 0.2 unit on log(IC50). Affinities for the 5-HT1A receptors were in the nanomolar range for the best compounds ((+)-11a,23) with a high selectivity versus other 5-HT (5-HT1B, 5-HT2, 5-HT3) or dopamine (D1, D2) receptor subtypes. As for the 3-amino-3,4-dihydro-2H-1-benzopyran series, the dextrorotatory enantiomer (+)-11a showed better affinity and selectivity for 5-HT1A receptors than its levorotatory analogue (-)-11a. Compound (+)-11a proved in vitro to be a full agonist and in vivo to be active in various comportmental tests predictive of psychotropic activity, such as the forced swim test and the tail suspension test, and is currently under complementary investigations.

Comparison of sulfobutylether- and sulfated-β-cyclodextrins as additives for the chiral separation of basic spirobenzopyrans by capillary electrophoresis

“…The synthesis of 5-HT 1A agonists seems to be attractive due to their effects on anxiety and depression behavioral disorders [32,33]. A recent study [32] has led to new therapeutic agents, such as 5¢-methoxy-3¢,4¢-dihydrospiro[pyrrolidine-2,3¢(2¢H)-benzopyran] (I) as a precursor or 1-n-propyl-5¢-methoxy-3¢,4¢-dihydrospiro[pyrrolidine-2,3¢(2¢H)-benzo-pyran] (II), which demonstrates a rather good affinity on the 5-HT 1A receptor and high selectivity in contrast to other receptors (Fig.…”

A Catalyst‐Free Cycloaddition Reaction: Access to Spiro[chroman‐3,2’‐indene‐1’,3’‐dione] Scaffolds

“…Myristinin A, a flavonoid isolated from Myristica cinnamomea and Knema elegans , shows antifungal and DNA polymerase β inhibitory activities (Scheme , A) . Spiro chroman (‐)‐S22178 is developed as a potent 5‐HT1A agonist to potentially treat anxiety and depression (Scheme , B) . Fredericamycin A is reported as an antitumor compound with antibiotic properties (Scheme , C) and biphenyl‐based spirocyclic ketone is widely used as new anticancer agent (Scheme , D) .…”

5-Substituted 3,4-dihydro-3-amino-2H-1-benzopyran derivatives: synthesis and interaction with serotoninergic receptors

“…Structures of derivatives I (Besson et al 1993 ;Podona et al 1994 ;Comoy et al 1996). sleep disorders, depression and schizophrenia (Eglen et al 1997). Therefore, the discovery of agonists and antagonists of 5-HT 7 receptors may have clinical utility.…”

“…A range of N-disubstituted (5-methoxy-3,4-dihydro-2H-1-benzopyran-3-yl)amino derivatives (I ; Figure 2), prepared in our laboratory, exhibited high affinity for 5-HT 1A receptors (Besson et al 1993 ;Podona et al 1994 ;Comoy et al 1996). Moreover, screening of derivatives I against the cloned human 5-HT 7 receptor showed, for some of them such as 5-methoxy-3,4-dihydro-3-di-npropylamino-2H-1-benzopyran (5-MeO-DPAC) and S20244 ( Figure 3), significant affinity for this receptor (Rezaie et al 1998a).…”