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Vol. XXIV No. 5 SCIENTIA SINICA May 1981 STUDIES ON SYNTHESIS AND RELATIONSHIP BETWEEN ANALGESIC ACTIVITY AND RECEPTOR AFFINITY FOR 3-METHYL FENTANYL DERIVATIVES” Jin Wenarso (x8), Xv Heno (i 3), Zev Youoweno (see0%), Fane Sunan CHIP), Xta Xincun (BX), Heanc Zuonorone (205), Ge Banowwn (85g) ano Cia Zarquana (ssi) (Shaaghai Tnattate of Materia Medica, Aoademia Sinica) Received December 17, 1978 Ansmaact Tu the prevent paper, the synthesie and the gnalgete actilty (mico, Lp. hot plate test) of the derivatives of S-methy] fentanyl are briefly described. Compound 2902, els-N-[J-(2-hydroxy- 2.phenylethyl) -8.methyl-4 pipridyl].N phonylpropionamide (es: 8.methyl/4-N-phenploropionamide) found to be the most potent analgesic agent in this series eynthesized by our laboratory (HD u=0.0022 mg/kg). The analgecie activity of 7802 is 28 times moro potent than that of fentany! and 6300 times more than that of morphine. The partition coefficients of 10 compounds fn the series are dotermined by high performance lignid chromatography (HPLC) and their log p values are about 8 ‘Thore are uo regular relationships between the analgesie activity and partition cocfficints, Study on the speeitie binding of 8 out of the above 10 compounds to crude synaptic plasma membrane (Frfraction) of mouse brain demonstrates that there is au ‘exellent statistical linear correlation (r==0.908) between the analgesic potency and the spocifio binding affinity. The result shows that the analgesic poteney of the derivatives of this aories fe mainly dependent on binding affinity for opiate receptor. I. Iwmropueniox Fentanyl is a potent analgesic agent-characterized by high potency, rapid onset and short duration of action and is extensively used in clinics"*”, It is known that the anal- ‘gesie activity of 4-phenylpiperidine analgesies was obviously enhanced when 3-methyl ‘group was introduced into its piperidine ring! (Table 1). ‘The authors of this paper hypothesized that introduction of @ methyl group into 3-position of piperidine ring of fentanyl might also enhanee analgesie activity, and thus we synthesized primarily four Semethyl fentanyl derivatives in 1972. Sure enough, the analgesic poteney of cis-3-methy! fentanyl is approximatly 5 times more active than that of fentanyl. Sinee then, modi- fieations of 3-methyl fentanyl in various positions have been tried, three kinds of strue- * Some original works have been reported in the following symposiums: (4) Spmposiam on **Ner= ‘vous System Droge’? (Beijing, China, November, 1978), (ii) Symposium on ‘Drug Acting on Central Nervous System” (Beljing, China, August, 1970), and i!) Annual Meoting of Chinese Pharmaco- Togical Society (Chengda, China, September, 1979). No.8 SMBTHYL FENTANYL DERIVATIVES m tural features were synthesized and their pharmacological properties were studied, Tt is also interesting to note that the analgesic effects of opiate analgesies are dependent ‘on two principal factors: (i) the analgesie poteney is correlated with lipid solubility of the analgesics. In general, the analgesics of high lipid solubility cross the blood-brain- barrier easily and then reach the site of action; (it) the analgesic potency is correlated swith the treceptor affinity of the analgesies. Therefore, the partition coefficients of a series of typical 3-methyl fentanyl derivatives were determined by HPLC and the specific binding affinity for mouse Brain opiate receptor of some compounds selected rom them was determined in order to reveal the relationship of the analgesie potency of these derivatives to their partition coefficient and receptor affinity. Tobie 1 Compound Potency aio CMorphine=1) oy 1 oon $ cH ° mA ‘ovout leans) 1 Ne CHN/Sovont (i) 5 Seats /QCHOHOHN “Ne \ “\_/Socont 1000 on Son, I Cunssmy 1, Synthesis ‘3-methyl fentanyl was synthesized by using N-benzyl-3.nethyl-piperidone as starting material. ‘The process is outlined in Fig. 1. On the basis of 3.methyl fentanyl synthe- sized, the various structure modifications in the L-position of piperidine ring and in the phenyl ring of 4N-phenylpropionamide moiety in 3-methyl fentanyl were performed. A total of 83 compounds of 3-methyl fentanyl derivatives has been synthesized so far. The ‘major compounds are of three types. The general structure formulas are shown as in Fig. 1. By further reduction of Schiff base, cis and trans isomers could be obtained. In general, the chair conformation of the piperidine ring is moro stable, Asvuming a chair conformation for the piperidine ring, one would expeet that the most predominant eon- former would have an equatorial 4-N-COEt group with an axial $-Me group for the cis | Ph na SOUENTIA SINICA Fe compound and an equatorial 3-Me group for the trans compound. Isomers TV, and IV, were separated by fractional erystallization. Diastereoisomers assignment was made on the basis of the 100-MH, nmr spectrum, In order to reduce interference of acyl pro- ton to other moiety, higher melting point compound IV, was hydrolyzed with 48% HBr, and the compound III, was obtained. After treatment with chemical shift reagent and double irradiation, compound III, showed the 3-proton chemical shift eentered at 02.09; the 4-proton chemical shift centered at 03.07; Jus, 5 eps. Therefore we confirmed that compound II, was the cis form and the other compound IIT, with lower melting point was the trans form, Concerning the analgesic activity of the isomers, cis isomer was 6.6 times more potent than fentanyl, but the trans isomer was only 1.6 times (Table 2). ‘The result obtained in our laboratory in 1972 was similar to the works lately described in literature by Riley ca al! and Van Baver el a. Based! on the pharmscological results mentioned above, the compounds were all cis form, most of which were found to have a typical morphine-like activity. ‘When debenzylated cis isomer type Vs reacted with various kinds of halogenated