J . Med. Chem. 1981,24,788-794
788
Epimeric cis-Decahydroquinoline-5-carboxylic Acids:’ Effects on y-Aminobutyric Acid Uptake and Receptor Binding in Vitro Donald T. Witiak,* Kuniyuki Tomita, Raymond J. Patch, Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210
and S. J. Enna Departments of Pharmacology and of Neurobiology and Anatomy, The University of Texas, Medical School, Houston, Texas 77025. Received January 19, 1981
The syntheses for two cis-decahydroquinoline-5-carboxylicacid epimers (1 and 2) which contain the =N(C)&02H (7-aminobutyric acid; GABA) moiety are described. Both intra- and intermolecular [4 + 21 cycloaddition reactions were employed for the construction of key intermediates. ‘H NMR studies provided evidence for the preferred solution conformations of the two diastereomers. Pharmacological studies revealed that these isomers have little affinity for GABA receptors in vitro relative to GABA agonists. However, expected but weak stereoselective activity was observed when these analogues were assessed for their ability to inhibit high-affinity [3H]GABA uptake into rat brain synaptosomes. These data are discussed in light of structure-activity studies of other neurotransmitter analogues, and a preliminary hypothesis based upon conformational analysis is presented to explain the results.
The four diastereomers (1-4) of decahydroquinoline-5-
la
-
Scheme I
0
2b
3
-NC02CH,Ph
R
t
H.OiO
+
H
‘-NHCO2CH2Pi
7
carboxylic acid are zwitterionic species2which contain a y-aminobutyric acid (GABA) moiety [=N(C),CO,H]. While it is possible that these stereoisomers may serve as probes to s t u d y GABA-mediated neurotransmission, i t
would not be expected that such structures should have the intrinsic activity of a GABA agonist.34 cis-Decahydroquinoline epimers 1 and 2 are conformationally flexible, whereas trans isomers 3 and 4 are rigidly fixed. In the present report the syntheses for cis-1 and -2 are described, and evidence for their preferred solution conformations as structures la and 2a is presented. Additionally, preliminary biochemical data are discussed con-
-
Me02C+x
1
5a, R = Me b, R = H
28; R = OCH,Ph Scheme IIa
c-’
c’-T 0
0
i/
11 /
-C I
13
0,Me
12 A- - 1
/
C02Me
6
14 15 a = H,/Pd.BaSO,, toluene; b = DIBAL, toluene (-60 “C);c = methyl (triphenylphosphoranylidene)acetate,benzene; d = NaI, DMF; e = CH,=CHCH=CHNHCO,Et (16), a
A preliminary account of the chemistry of this series has been presented. See K. Tomita and D. T. Witiak, in “Abstracts of PaDers”. 179th National Meeting of the American Chemical Society,’Houston, TX, Mar 23-6, 1980, American Chemical Society, Washington, DC, 1980, Abstr ORGN 26. Compounds were studied as their hydrochloride salts. Cyclic compounds are named according to Chemical Abstracts’ convention wherein the substituent at the lowest carbon number (Le., 4a in bicyclic compounds) is arbitrarily assigned the a notation and all other substituents are defined (aor 8) relative to this position. G . A. R. Johnston, R. D. Allan, S. M. E. Kennedy, and B. Twitchin in “Gaba-Neurotransmitters: Pharmacochemical, Biochemical and Pharmacological Aspects”, P. KrogsgaardLarsen, J. Scheel-Krtiger, and H. Kofod, Ed., Academic Press, New York, 1979, p 149. P. Krogsgawd-Larsenand A. V. Christensen, Annu. Rep. Med. Chem., 15, 41 (1980). P. Krogsgaard-Larsen, T. Honor6, and K. Thyssen, in ref 3, p 201.
J. P. O’Donnell, D. A. Johnson, and A. J. Azzaro, J . Med. Chem., 23, 1142 (1980). 0022-2623/81/1824-0788$01.25/0
NnH nMF . I
cerning the effect of these compounds on [3H]GABAreceptor binding7 and high-affinity [3H]GA13A uptake i n rat brain tissue.8 A preliminary hypothesis is presented to explain the biological properties of 1 and 2, though confirmation must await further studies employing 3 and 4 in these biological systems. Furthermore, a parallelism i n stereostructure-activity relationships with small (cyclopropane) vs. larger ring systems i n cholinergic vs. GABAergic systems is discussed. T h i s expected correlation and the possibility that indirectly acting anticonvulsants may be obtained through use of large lipophilic moieties pro(7) s.J. Enna and s. H. Snyder, Mol. Pharmacol., 13,442 (1977). (8) J. P. Bennett, W. J. Logan, and S. H. Snyder, J . Neurochem., 21, 1533 (1973).
0 1981 American Chemical Society
Epimeric cis-Decahydroquinoline-5-carboxylicAcids
vided the impetus for our effort in this area. Synthetic Chemistry. Synthesis of target analogue cis-1, which may be epimerized to cis-%,was carried out using both [4 21 intramolecular and intermolecular cycloadditions (Scheme I). Intramolecular reaction affording desired intermediate 5 was modeled after the OppolzerFrBstlgsynthesis wherein the vinylic carbomethoxy group in 6 was replaced by H or Me. Intermolecular reaction of dienamide 7 with dienophile 8 initially affording intermediate 10 and ultimately cis-1 was based on Danishefsky and Hershenson'slo synthesis of isogabaculine, which employed the nitrodienophile 9. Syntheses for pumiliotoxin-C1la.band (f)-perhydrogephyrotoxin1lChave been developed by Overman et al., wherein the approach is similar to the preparation of cis-1 using the intermolecular Diels-Alder reaction but differs in detail. Dienamide 6 was synthesized from 1615and methyl 6iodo-2(E)-hexenoate (15) in 37% yield12 using NaH in DMF at room temperature (Scheme 11). Hexenoate 14, which served as precursor to 15, was prepared using known method01ogy'~J~from either 4-chlorobutyryl chloride (11) or ethyl 4-chlorobutyrate (12) via intermediate chloroaldehyde 13. Ylide reaction with 13 afforded hexenoate 14 in 47% yield. Reaction with NaI in DMF yielded iodo ester 15 in 78% yield. Conversion of 6 to cis-octahydroquinoline 5a in approximately 60% yield was carried out by heating (toluene; 200-210 "C) in a sealed tubeg for 14 h and was accompanied by the formation of a trace amount of trans-17 isomer.
Journal of Medicinal Chemistry, 1981, Vol. 24, No. 7 789
Scheme 111"
+
R
,I,
'C0,Et 1
17, R = C0,Me 18, R = CH,OH 19, R = CH,02C[3,5-(N0,),]Ph 20. R = CHO 21; R = CO,H
22, R = CH,OH 23, R = CHO 24, R = H
Separation of minor adduct trans-17 from cis-5a was difficult and could only be accomplished by reduction to 18 followed by formation of the 3,5-dinitrobenzoate ester 19. Pure 18, derived from hydrolysis of 19, was converted to 20 with pyridinium chlorochromate16and subsequently to 21 using Ago and NaCN.17 Acid 21, upon reaction with diazomethane, served as a source of pure trans-17. Hydrogenation of pure trans-18 afforded 22 whose 'H NMR spectrum was characteristically similar to the spectrum of authentic trans-decahydroquinoline24.18J9 Furthermore, W. Oppolzer and W. Frostl, Helu. Chim. Acta, 58,590 (1975). S. Danishefsky and F. M. Hershenson, J. Org. Chem., 44,1180 (1979). 100, (a) L. E. Overman and P. J. Jessup, J. Am. Chem. SOC., 5179 (1978); (b) L. E. Overman and P. J. Jessup, Tetrahedron Lett., 1253 (1977); (c) L. E. Overman and C. Fukaya, J. Am. Chem. SOC.,102, 1454 (1980). Reduced yields were attributed to concurrent formation of substantial quantities of methyl 8-cyclopropylacrylate. R. B. Loftfield, J. Am. Chem. SOC.,73,1365 (1951). L. I. Zakharkin and I. M. Khorlina, Tetrahedron Lett., 619 (1962). L. E. Overman, G. F. Taylor, C. B. Petty, and P. J. Jessup, J. Org. Chem., 43, 2164 (1978). E. J. Corey and J. W. Suggs, Tetrahedron Lett., 2647 (1975). E. J. Corey, N. W. Gilman, and B. E. Ganem, J. Am. Chem. SOC.,90, 5616 (1968).
26
29
1
30
33
32
34
35
II cis-2.HCI " a = methyl (triphenylphosphoranylidene)acetate, CHCl,; b = pyridinium chlorochromate, CH,Cl,; c = compound 7, toluene, A ; d = formylmethylenetriphenylphosphorane, toluene; e = H,, 10%Pd/C, MeOH; f = ethyl chloroformate, K,CO,; g = H,, 10%Pd/C, MeOH, HOAc; h = LDA, THF, -70 "C; i = NaOH, H,O; j = concentrated HCl, A ; k = concentrated HCl; 1 = benzyl chloroformate, K,CO,.
22 was converted to 24 via oxidation (pyridinium chlorochromate)16 to 23, followed by decarbonylation using tris(triphenylphosphine)rhodium(I) chloride.20 Alternatively, cis-1 was prepared by intermolecular [4 + 21 cycloaddition (Scheme I). Dienamide 715underwent reaction with methyl 4-oxo-2(E)-butenoate (8), affording 10 in approximately 65% isolated yield. Aldehyde 8 was prepared by reaction of glycoaldehyde (25) with methyl (triphenylphosphoranylidene)acetate,followed by pyridinium chlorochromate16oxidation of intermediate methyl 4-hydroxycrotonate (26)23(Scheme 111). Coupound 8 also (18) H. Booth and A. H. Bostock, J. Chem. SOC.,Perkin Trans. 2, 615 (1972). (19) The 8a proton resonance signal of 22 was found at 6 3.20 in the form of a triplet (J= 12 Hz) of doublets (J= 4 Hz). Likewise, a similar 8a proton resonance signal pattern for 24 was observed at 6 3.08, whereas the 8a-proton resonance signal pattern for epimer 16 was found under the methylene proton resonance signal of the ester function as an unresolved doublet (J = 11 Hz)at approximately 6 4.15. The proton resonance signal for the 5-H proton bonded to the carbon substituted with R in 22 and 23 was masked under the alkyl proton resonance envelope and, thus, the stereochemistry for R (cis to the 4a axial proton) was tentatively assigned based on the cyclization mechanism. (20) J. Tsuji and K. Ohno, Tetrahedron Lett., 3969 (1965). (21) W. R. Roush, A. I. KO,and H. R. Gillis, J.Org. Chem., 45,4264 (1980). (22) W . Oppolzer, Angew. Chem., Int. Ed. Engl., 16, 10 (1977). (23) R. Rambaud, Bull. SOC.Chim. Fr., 1, 1317 (1934).
790 Journal of Medicinal Chemistry, 1981, Vol. 24, No. 7
Table I. Effect of cis-l.HC1 and cis-2.HCl on [ 3H]GABA Receptor Binding t o Rat Brain Membranesa % displacement of concn, specifically bound compd IIM [ 'HIGABA GABA 0.01 48 t 5 muscimol 0.01 86 * 3 100
