Crystal structure and metabolic activity of 4-(thien-2-yl)-2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethoxycarbonylphenylmethylester

In this condensed 1,4-dihydropyridine derivative, which exhibits metabolism-regulating activity, the 1,4-dihydropyridine ring adopts a flattened boat conformation while the cyclohexenone ring is in an envelope conformation. Molecules in the crystal are assembled into chains along the a-axis direction via N—H⋯O hydrogen bonds.


Chemical context
Up to now, the 2-methyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic esters in the class of condensed 1,4-dihydropyridine (DHP) derivatives have been relatively poorly studied. Monocyclic DHPs are very commonly known as cardiovascular regulating and hypotensive compounds (Swarnalatha et al., 2011). The title compound is an original substance with a specific ligand effect on the metabolismregulating free fatty acid receptor 3 (FFAR3 or GPR41). At the same time, it does not act on other metabolite-sensing receptors such as FFAR2 (GPR43) or the hydroxycarboxylic receptor 2 (HCA2) having similar pharmacological effects. Fig. 1 shows the molecular structure of the title compound. A two-component disorder is found for the thienyl fragment, which assumes two orientations differing by a 180 rotation around the C7-C16 bond. The major component has a refined occupancy of 0.7220 (19) and is that shown in Fig. 1. The 1,4-dihydropyridine ring adopts a flattened boat conformation while the cyclohexenone ring is in an envelope conformation. Atoms C7 and N1 deviate by 0.298 (3) and 0.135 (3) Å , respectively, in the same direction from the mean

Metabolic activity
The title compound possesses considerable and specific activity as a ligand of FFAR3. At 50 mM concentration, the compound inhibits forskolin-stimulated level of cAMP by 60% in recombinant cells expressing FFAR3. The compound through FFAR3 inhibits the cAMP-dependent pathway by inhibiting adenylate cyclase activity and decreasing the production of cAMP, which results in decreased activity of cAMP-dependent protein kinase. The activation of FFAR3 could be involved in the production of leptin by adipose tissue, regulation of intestinal immunity and secretion of the PYY peptide and GLP-1 hormone by enteroendocrine cells (Ichimura et al., 2014 Symmetry code: (i) x þ 1 2 ; Ày À 1 2 ; z.

Figure 2
A packing diagram of the title compound, viewed along the b-axis direction. N-HÁ Á ÁO hydrogen bonds are shown as dashed lines.

Figure 3
Reaction scheme for the title compound 1.

Figure 1
The molecular structure of the title compound with the atom-numbering scheme and 50% probability displacement ellipsoids. Only the major component of the disordered thienyl fragment is shown.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. All hydrogen atoms bonded to carbon atoms were placed in calculated positions and included as riding contributions in the final stages of refinement [Csp 3 -H = 0.95-1.00 Å with U iso (H) = 1.2U eq (C) for methine and methylene groups, and U iso (H) = 1.5U eq (C) for methyl groups]. The hydrogen atom bonded to the nitrogen atom was identified as the strongest peak in the electron-density difference map and was refined isotropically. There is a twocomponent disorder in the thienyl group with the ring assuming two positions with opposite orientations. The two orientations were refined as rigid groups using an accurate determination of the geometry of the thienyl group taken from CSD structure UWIYUW (Anil et al., 2016) as the model. Refinement of the group occupation factor (the second free variable in the FVAR instruction of SHELXL) gave the value of 0.7220 (19).   program(s) used to refine structure: SHELXL2018/1 (Sheldrick, 2015); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012); software used to prepare material for publication: publCIF (Westrip, 2010).

Special details
Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å 2 )
x y z U iso */U eq Occ. (