Nicole T. Hatzenbuhler

Advances toward New Antidepressants with Dual Serotonin Transporter and 5-HT1A Receptor Affinity within a Class of 3-Aminochroman Derivatives. Part 2

Novel compounds combining a 5-HT 1A moiety (3-aminochroman scaffold) and a 5-HT transporter (indole analogues) linked through a common basic nitrogen via an alkyl chain attached at the 1- or 3-position of the indole were evaluated for dual affinity at both the 5-HT reuptake site and the 5-HT 1A receptor. Compounds of most interest were found to have a 5-carbamoyl-8-fluoro-3-amino-3,4-dihydro-2 H-1-benzopyran linked to a 3-alkylindole (straight chain), more specifically substituted with a 5-fluoro (( R)-(-)- 35c), 5-cyano ((-)- 52a), or 5,7-difluoro ((-)- 52g). Several factors contributed to 5-HT 1A affinity, serotonin rat transporter affinity, and functional antagonism in vitro. Although most of our analogues showed good to excellent affinities at both targets, specific features such as cyclobutyl substitution on the basic nitrogen and stereochemistry at the 3-position of the chroman moiety seemed necessary for antagonism at the 5-HT 1A receptor. Branched linkers seemed to impart antagonism even as racemates; however, the potency of these analogues in the functional assay was not desirable enough to further pursue these compounds.

Synthesis and structure–activity relationship of novel lactam-fused chroman derivatives having dual affinity at the 5-HT1A receptor and the serotonin transporter

The structure-activity relationship (SAR) for three series of lactam-fused chroman derivatives possessing 3-amino substituents was evaluated. Many compounds exhibited affinities for both the 5-HT(1A) receptor and the 5-HT transporter. Compounds 45 and 53 demonstrated 5-HT(1A) antagonist activities in the in vitro cAMP turnover model.

Synthesis, Potency, and in Vivo Evaluation of 2-Piperazin-1-ylquinoline Analogues as Dual Serotonin Reuptake Inhibitors and Serotonin 5-HT1A Receptor Antagonists

On the basis of the previously reported clinical candidate, SSA-426 (1), a series of related 2-piperazin-1-ylquinoline derivatives 3-16 were synthesized and evaluated as dual-acting serotonin (5-HT) reuptake inhibitors and 5-HT1A receptor antagonists. In particular, compound 7 exhibits potent functional activities at both the 5-HT transporter and 5-HT1A receptor, good selectivity over the alpha1-adrenergic and dopaminergic receptors, acceptable pharmacokinetic properties, and a favorable in vivo profile.

The efficient synthesis of a bis-glycosylated steroid drug transport reagent : Methyl 3-β-amino-7α,12α-di(1'α-glucosyl)-5β-cholate (TC002)

The drug transport reagent, methyl 3-β-amino-7α, 12α-di(1′α-glucosyl)-5β-cholate (TC002) 1 was prepared in 15% overall yield from pentaacetyl glucose and methyl cholate. Pentaacetyl glucose was converted to glucosyl sulfoxide 2 in 56% overall yield. Methyl cholate was converted to methyl 3-β-azido cholate 3 in 67% yield. Bis-glycosylation of 3 with 2 followed by a single step reduction provided 1.

Preclinical characterization of WAY‐211612: a dual 5‐HT uptake inhibitor and 5‐HT1A receptor antagonist and potential novel antidepressant

Background and purpose:  As a combination of 5‐HT selective reuptake inhibitor (SSRI) with 5‐HT1A receptor antagonism may yield a rapidly acting antidepressant, WAY‐211612, a compound with both SSRI and 5‐HT1A receptor antagonist activities, was evaluated in preclinical models.