Synthesis of Novel 5-Substituted 3-Amino-3,4-dihydro-2H-1-benzopyran Derivatives and Their Interactions with the 5-HT_1A Receptor

Abstract

A series of new enantiomerically pure 3-amino-3,4-dihydro-2H-1-benzopyrans (3-aminochromans) has been synthesized from (R)- and (S)-5-methoxy-3-amino-3,4-dihydro-2H-1-benzopyran. The absolute configuration of the respective (R)- and (S)-enantiomers was deduced from X-ray crystallography of (R)-3-(N-isopropylamino)-5-methoxy-3,4-dihydro-2H-1-benzopyran, (R)-9a. Various 5-substituents were introduced via palladium-catalyzed carbonylation of N-substituted 3-amino-5-trifluoromethanesulfonyloxy-3,4-dihydro-2H-1-benzopyran. The effect of N- and 5-substitution on affinity for the 5-HT1A receptor was evaluated in competition experiments using rat hippocampal membranes and [3H]8-OH-DPAT as radioligand. Selected compounds were also tested for their affinity to the D1 (rat striatum), D2 (rat striatum), D2A (human cloned), and 5-HT2A (rat cortex) receptors. The intrinsic activity of the compounds was evaluated by measuring their effect on VIP-stimulated cAMP production in GH4ZD10 cells stably transfected with the 5-HT1A receptor. High-affinity compounds with high selectivity for the 5-HT1A receptor were found among structures substituted with carboxylate esters, amides, and ketones in the 5-position. Primary and secondary amines bound with lower affinity than tertiary amines. Larger substituents were well-tolerated by the receptor, but the smaller N-ethyl-N-isopropyl bound with lower affinity. Generally, the (R)-enantiomers displayed higher affinity for the 5-HT1A receptor than the corresponding (S)-enantiomers. In the present series of compounds, both full and partial agonists were found.

Electrochemical and spectroscopic characterisation of amphetamine-like drugs: Application to the screening of 3,4-methylenedioxymethamphetamine (MDMA) and its synthetic precursors

“…This group is readily attached to the nitrogen atom by reaction of the primary amine with trifluoroacetic anhydride ((CF 3 CO) 2 O) in the presence of a base (triethylamine or pyridine), at low temperature [30,31]. Then, after N-alkylation with methyl iodide, the resulting N-methyltrifluoroacetamide is easily cleaved (N-deacylation) in basic conditions [30].…”

Development of a Process for a Chiral Aminochroman Antidepressant: A Case Story

“…The structural features of this disubstituted chroman (or 3,4-dihydro-2 H -1-benzopyran) besides its chirality are (i) the unsymmetrically substituted tertiary amine functionality in position 3 and (ii) the secondary carboxamide group attached to C-5. As is frequently observed also the stereoisomers in this case exhibited a pronounced difference in pharmacological properties which eventually led to choosing the ( R )-enantiomer as the desired form …”

Quantitative Pharmacology or Pharmacokinetic Pharmacodynamic Integration Should Be a Vital Component in Integrative Pharmacology

“…Furthermore, potential drug interactions will be different for the parent compound and metabolite. Figure 2 illustrates procedures used to detect the pharmacodynamic effects of a possible metabolite of the 5-HT 1A receptor agonist ebalzotan (Hammarberg et al, 2000). It was assumed that the metabolite possessed the same pharmacodynamic profile as its parent compound, albeit with possible differences in potency and/or efficacy.…”