Design, synthesis, and biological evaluation of 3,4,5-trimethoxyphenyl acrylamides as antinarcotic agents

Figures & data

Figure 1.  Chemical structures of cinnamic acid (2), p-coumaric acid (3), ferulic acid (4), sinapic acid (5), and curcumin (6).

Scheme 1.  (a) (CH₃)₂SO₄, KOH, 10°C, 1 h, and then reflux 5 h (60%); (b) (Ph₃P⁺=CHCO₂C₂H₅)Br⁻, KOH, DMSO, 16 h (52%); (c) amines, HOBt, EDCI, TEA, CH₂Cl₂, room temp., 2 h (67–86%).

Figure 2.  Effects of 3,4,5-trimethoxyphenyl acrylamides on naloxone-induced jumping behavior in morphine-dependent mice. TMCA and 3,4,5-trimethoxyphenyl acrylamides (5 mg/kg, i.p.) and (+)8-OH-DPAT (0.5 mg/kg, i.p.) were injected 30 min before morphine injection (10 mg/kg, i.p.) for 7 days. On the 7th day, naloxone (5 mg/kg, i.p.) was injected 6 h after final drug administration. The number of jumps in a 30 min interval was counted after naloxone injection. *p < 0.05, **p < 0.01 in comparison with morphine only group.

Table 1.  Serotonin (5-HT) receptor and transporter binding affinities of 3,4,5-trimethoxyphenyl acrylamides.

Compound	Receptor binding affinity (IC50, μM)^a
	5-HT1A	5-HT2A	5-HT2C	5-HT6	5-HT7	5-HT transporter
1a	5.6	> 10	> 10	> 10	> 10	> 10
1b	5.9	> 10	> 10	> 10	> 10	> 10
1c	4.9	> 10	> 10	8.8	> 10	> 10
1d	3.8	> 10	> 10	9.4	> 10	> 10
1e	1.2	> 10	8.8	> 10	> 10	> 10
1f	2.1	6.8	4.5	5.0	5.6	6.7
TMCA^b	7.6	> 10	2.5	> 10	> 10	> 10

^aAll compounds were tested at a maximum concentration of 10 μM and their binding affinities were calculated as an IC₅₀ (μM) value.

^b3,4,5-Trimethoxycinnamic acid

Figure 3.  WAY 100635 inhibits 3,4,5-trimethoxyphenyl acrylamide-induced pERK expression. Cultured neuronal cells were treated with 3,4,5-trimethoxyphenyl acrylamides (10 μM) and/or WAY 100635 (1 μM) for 30 min. The expression of pERK was examined by Western blot analysis.