Analgesic and Anti-Inflammatory Effects of 1-(4'-Dimethylaminophenyl)-6, 7-Dimethoxy-1,2,3,4-Tetrahydroisoquinoline Hydrochloride

It is known that natural isoquinoline alkaloids are widely used in pharmacology and have a variety of biological activities1. At the same time, synthetic analogs of isoquinoline alkaloids are of great interest, among which compounds have been identified that are promising agents that modulate the activity of the dopamine and serotonergic systems2,3, showing cardiprotective4 effect, antiproliferative5 and analgesic6 activity. Currently, in practical medicine, aspirin and anlagen are widely used as non-narcotic analgesics7. However, the low intensity of the analgesic effect, the lack of an analgesic effect in certain types of pain (thermal, mechanical, and other acute pain) and the large number of side effects caused by long-term use limits the scope of their application. The properties of 1-(4’-dimethylaminophenyl)- 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3) have not been previously described in the scientific literature. The analgesic and anti-inflammatory activity of 1-(4'-dimethylaminophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3) was studied under conditions of thermal (hot plate test) and chemical (vinegar writhing test) irritation, anti-inflammatory activity - on the model of acute inflammatory arthritis. As a result of the studies, it was found that the compound 1-(4'-dimethylaminophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline in various doses has an analgesic and anti-inflammatory effect. 1-(4'-Dimethylaminophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3) showed a pronounced anti-inflammatory effect at a dose of 0.5 mg/kg, 3.3 times greater than the effect of diclofenac sodium. It has been shown that 1-(4’-dimethylaminophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3) has a pronounced analgesic and anti-inflammatory activity and can be used in medical practice as a non-narcotic analgesic.

The understanding the mechanisms of pathological pain and the search for new highly effective pharmacological agents with minimal side effects is important in solving the problem of pain relief. Non-narcotic analgesics are most commonly used for the treatment of mild to moderate pain of various etiologies. Over the world more 30 million people daily take nonnarcotic analgesics, including non-steroidal antiinflammatory drugs (NSAIDs) 8 . According to the results of observations, all representatives of non-narcotic analgesics administered in equivalent doses, have relatively similar efficacy and differ mainly in individual tolerance and the ability to cause side reactions: damage gastrointestinal tract, destroy platelet aggregation, renal function, and cause negative effect on the liver and circulatory systems 9 .
Currently, acetylsalicylic acid and sodium metamizole are most widely used in medicine 10 . However, low analgesic effect, absence of an analgesic effect for some types of pain (thermal, mechanical, and other acute pains) and the large number of side effects caused limit the scope of their application.
A mixture of 26.3 g (0.14 mol) of 3,4-dimethoxyphenylethylamine (1) with 21.67 g (0.14 mol) of 4-dimethylaminobenzaldehyde (2) was heated at 80°C in an oil bath with a contact thermometer for 2 hours with a reverse refrigerator. After cooling to room temperature, 100 ml of trifluoroacetic acid was added to the reaction mixture and boiled with a reverse refrigerator for 4 hours. The course of the reaction was controlled by TLC. Next, the reaction mixture was cooled with ice and alkalized with a 10 % aqueous NaOH solution to a pH of 9-10. The amine was exhaustively extracted with chloroform. After distilling the chloroform, the crude product was dissolved in acetone and acidified conc. HCI to pH 5-6. The precipitated hydrochloride precipitate Scheme 1.  Experimental studies were conducted in accordance with the requirements of the «European Convention for the Protection of Animals Used for Experimental and Scientific Purposes» 13 .
The studied compounds were administered intragastrically using non-traumatic metal probe 60 minutes before the chemical or thermal irritation.
Analgesic activity of the studied compound was tested on 80 white outbred mice weighing 18-20 g in compare with acetylsalicylic acid and sodium metamizole in the acetic writhing and hot plate tests.
In the hot plate test 1-(4'-dimethylamin o p h e n y l ) -6 , 7 -d i m e t h o x y -1 , 2 , 3 , 4 -t e t r a hydroisoquinoline hydrochloride (3)  The acetic writhing test is used to assess visceral pain. The pain was caused by intraperitoneal administration of 1% acetic acid solution, which leads to the appearance of the "writhing" syndrome. The number of writhing in animals of the experimental and control groups was calculated within 20 minutes.
Anti-inflammatory activity of the compound was determined on white male rats weighing 200-220 g on a model of acute inflammatory edema caused by injection of 0.1 ml 2% aqueous solution of formalin into the rat's hind paw. The volume of the paw was measured oncometrically before the start of the experiment and at maximum development of edema in 3 hours after the injection of formalin. The studied substance was administered intragastrically in an hour before the introduction of formalin. The activity of the compound and the comparison drug diclofenac sodium was evaluated by the suppression of paw edema.

RESULTS
In the hot plate test, 1- The results of the studies are presented in Table 1.
It was found that the studied compound exhibits a pronounced analgesic effect on the model of acetic writhing. The average effective dose (ED 50 ) for suppressing the number of writhing caused by intraperitoneal administration of acetic acid was 0.5 mg/kg, and for metamizole sodium-180.5 mg/kg (Table 2).
Thus, the studied compound in the acetic writhing test is 36 times more effective (ED 50 ) and 13 times more safe (LD 50 /ED 50 ) than metamizole sodium. A higher analgesic index of the investigated indicates on its greater selectivity and safety compared to metamizole sodium.