Antihistamines, phenothiazine-based antipsychotics, and tricyclic antidepressants potently activate pharmacologically relevant human carbonic anhydrase isoforms II and VII

Figures & data

Figure 1. (A) Co-crystal structure of hCA II (yellow) in complex with histamine (1, shown in green) (PDB 1AVN).³⁶ (B) Focus on the hydrogen bond network linking the Zn²⁺-bound water molecule to 1 (PDB 1AVN). (C) Schematic of CA activation mechanism for histamine-like compounds binding to the activator binding site A. Histamine (or analogous CAAs) bind to the activator binding site A and, through their PSM, facilitate proton transfer from Zn²⁺-bound H₂O to the external medium. (D) Co-crystal structure of hCA II (yellow) in complex with D-Trp (shown in light blue) bound to (PDB 3EFI).⁴⁰ (E) Focus on the hydrogen bond network linking the Zn²⁺-bound water molecule to D-Trp (PDB 3EFI). (F) Schematic of CA activation mechanism for D-Trp-like compounds binding to the activator binding site B. D-Trp (or analogous CAAs) bind to the activator binding site B and, through their PSM, facilitate proton transfer from Zn²⁺-bound H₂O to the medium. In panels (A), (B), (D), and (E) the Zn²⁺ atom is shown as a black sphere, water molecules are displayed as red spheres, and polar interactions are depicted in purple.

Figure 2. Chemical structures of histamine (1) and compounds 2–18 evaluated in this study as CAAs.

Table 1. hCA I, II, IV and VII activation with compounds 2–18 by a stopped-flow CO₂ hydrase assay. Histamine (1) used as reference CAA.

Compd	KA (µM)^a				Literature Data
	hCA I	hCA II	hCA IV	hCA VII	CNS action	Reference(s)
1	2.1	125	25.3	37.5	+	^67
2	>50	>50	>50	4.7	+	^68^,^69
3	10.2	28.6	30.2	3.4	+	^70^,^71
4	>50	13.7	45.0	9.1	+	^72
5	>50	7.0	>50	29.5	+	^69^,^73
6	>50	4.8	>50	9.8
7	>50	3.7	>50	2.5	+	^74^,^75
8	>50	1.4	27.6	8.9
9	>50	2.8	43.9	5.2	+	^75^,^76
10	23.6	1.9	>50	4.8	+	^75
11	>50	21.2	>50	3.0	+	^77
12	>50	11.3	28.5	2.5	+	^78
13	9.3	2.0	27.8	3.1	+	^79
14	24.8	4.5	10.0	1.6	+	^80
15	>50	18.9	>50	13.3	+	^81^,^82
16	>50	11.7	>50	6.2	+	^82
17	>50	42.1	>50	4.9	+	^83
18	>50	45.6	>50	9.2	+	^84

^a Results of three different assays (n = 3; errors within ± 10% of the reported values). + means that there is evidence of BBB crossing and central action; no sign means that no literature data are available.

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