Structural insight into the inhibition of acetylcholinesterase by 2,3,4, 5-tetrahydro-1, 5-benzothiazepines

Figures & data

Scheme 1 General scheme for the synthesis of 2,3,4,5-tetrahydro-1,5-benzothiazepines (1–3).

Table I.  Steady-state inhibition of AChE by benzothiazepines 1–3.

Benzothiazepines	IC50 (μM) ± SEM	Ki (μM) ± SEM	Km (μM)	Kmapp (μM)	Vmax (μ mol L^− 1min^− 1)	Vmaxapp (mean) (μ mol L^− 1min^− 1)	Vmaxapp / Km (min^− 1 U^− 1)	Type of Inhibition
1	1.0 ± 0.002	0.8 ± 0.04	0.12	0.12	5	2.0	16.6	NC
2	1.2 ± 0.005	1.1 ± 0.01	0.12	0.12	5	2.1	17.5	NC
3	1.3 ± 0.001	1.5 ± 0.001	0.12	0.19	5	2.2	18.3	NC
Galanthamine*	0.5 ± 0.001	0.48 ± 0.002	0.12	0.12	5	2.5	20.8	MT

NC; Non-competitive, MT; Mixed-type, *Standard inhibitor of AChE; K_i (dissociation constant or inhibition constant) was determined from linear regression analysis by Dixon plot and secondary Lineweaver-Burk plot at various concentrations of benzothiazepine 1–3, K_m (Michaelis-Menten constant) is equal to the reciprocal of x-axis intersection, V_max (maximal velocity) is equal to the reciprocal of y-axis intersection of each line for each concentration of benzothiazepine 1–3 in the Lineweaver-Burk plot. The V_maxapp is equal to the reciprocal of y-axis intersection of each line for each concentration of benzothiazepine 1–3 in Dixon plot (Each point in Lineweaver-Burk, Dixon plot and in their secondary replots represents the mean of three experimental determinations).

Figure 1 Inhibition of AChE by benzothiazepine 1 (A) is the Lineweaver-Burk plot of reciprocal of initial velocities and reciprocal of four fixed ATCh concentrations in the absence (▪) and in the presence of 0.5 μM (▾), 1.0 μM (•), 2.0 μM (▴) of benzothiazepine 1. (B) is the Dixon plot at fixed ATCh concentrations, (▪) 0.4 mM, (▾) 0.2 mM, (•) 0.133 mM and (▴) 0.1 mM. (C) is the secondary replots of the Lineweaver-Burk plot, 1/ V_maxapp or slope and various concentrations of benzothiazepine 1.

Figure 2 LIGPLOTS showing interactions of the benzothiazepines 1–3 and galanthamine in the active site of AChE.