Activation of carbonic anhydrase isoforms involved in modulation of emotional memory and cognitive disorders with histamine agonists, antagonists and derivatives

Figures & data

Figure 1. CA activation mechanisms. Activators bind in the middle of the active site and contain a proton shuttle moiety (PSM) of the amine, imidazole or carboxylate type with an appropriate pKa for the proton transfer processes, usually in the range of 6–8.

Figure 2. Histamine 1 and derivatives 2–30 acting as histamine receptors agonists/antagonists (for reviews see refs.^33,34) investigated here as CAAs.

Table 1. hCA I, II, IV and VII activation with compounds 2–30 (Figure 2) by a stopped-flow CO₂ hydrase assay.²⁸ Histamine 1 used as standard.

Compound	KA (µM)^a				Data
	hCA I	hCA II	hCA IV	hCA VII	BBB crossing	Central action	Ref
1	2.1	125	25.3	37.5	–	+	^35
2	0.11	8.91	3.21	2.07
3	3.1	0.43	7.6	0.23
4	0.12	0.082	2.91	1.25		+	^36
5	0.36	5.4	5.13	0.39		+	^37
6	0.87	7.45	1.02	0.7
7	0.052	0.57	13.9	0.19
8	3.16	5.24	4.66	0.12		+	^38
9	3.15	7.66	8.01	0.52	+	+	^39
10	4.29	9.9	8.12	0.11	+	+	^40
11	0.88	8.39	9.07	0.43		+	^41
12	0.98	8.75	9.62	1.01		+	^42
13	8.79	6.3	8.54	0.59		+	^43
14	4.25	8.31	8.05	1.00		+	^44
15	>100	2.1	6.59	5.31	+	+	^45
16	0.72	2.14	3.3	0.10			^46
17	>100	>100	>100	>100		+	^47
18	>100	>100	32.3	45.5		+	^48
19	1.36	6.93	9.08	5.21
20	>100	>100	>100	>100	+	+	^49
21	>100	13.5	9.9	7.05	+	+	^50
22	>100	>100	>100	>100	+	+	^51
23	>100	9.82	15.9	>100		+	^52
24	5.23	9.62	6.78	2.05	+	+	^53
25	>100	>100	>100	>100
26	>100	>100	>100	>100	+	+	^54
27	>100	>100	>100	>100
28	>100	>100	>100	>100	+	+	^55
29	>100	>100	>100	>100	+	+	^56
30	>100	>100	>100	5.06	+	+	^57

^aFrom three different assays (errors within ± 10% of the reported values). – means no BBB crossing; + means that there are evidences of BBB crossing and central action; no sign means that no literature data are available.

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