a) Arene, RT, 10 h, workup: hydrochloric acid; b) amine , excess, ether, RT, 30 min
Scheme 1. Synthesis and chemical mechanism for the preparation of lactams from mucochloric acid.

Figure 1: CCK –gastrin antagonists

Figure 2: Overview of selective CCK1-, mixed- and CCK2 - antagonists. Graphical outline of the drug design from the original lead structure into the desired potent anti-inflammatory analgesic

Figure 3: Docking of CCK antagonist PNB-001 into the CCK2 receptor

Figure 4: Responses to CCK-5 in the absence and presence of PNB-001, using the rat duodenum assay; CCK-5, CCK-5 +10 nM PNB-001, CCK-5 +30 nM PNB-001, CCK-5 + 100 nM PNB-001; N = 2 for each data point

Figure 5: The inhibitory concentration-response curves of PNB-001, L-365,260 (standard) and lactame 16 for DSS stimulated contractions using the rat duodenum

Figure 6: Analgesic anti-inflammatory activity of PNB-001 on formalin induced pain in rats

Figure 7: Hotplate test of PNB-001 in mice by IP – administration

Figure 8: Tail immersion test of PNB-001 in mice by IP administration

Figure 9: Dose range of PNB-001 in the tail immersion test by PO administration using rats

Figure 10: Anxiolytic properties of PNB-001 in the X-maze model by PO administration

Lactam
X=
R=

CCK1 [mM]

CCK2 [mM]

7
H
Isobutyl-
0.020±0.01
1.2±0.3
8
Cl
Isobutyl-
0.008±0.01
0.4±0.2
15
H
Phenyl-
>10
>10
16
H
Benzyl-
0.85±0.03
0.020±0.005
17
Cl
Benzyl-
0.51±0.004
0.022±0.004

20
PNB-001

H
Phenylethyl-
>10
0.022±0.002
21
Cl
Phenylethyl
>10
0.030±0.001
Lorglumide
0.17±0.01
>10
L-356,260
0.25±0.01
0.003±0.001

Table 1: CCK binding affinity expressed in IC50 in micromolar using iodinated hot CCK8 as radioligands with cortex and pancreatic membranes; N=3