The Effect of Piperidinecarboxamide Derivatives ... - ACS Publications

The Effect of Piperidinecarboxamide Derivatives on Isolated Human Plasma Cholinesterase. III. Variation in the N1-Hydrocarbon Substituent. James G. Be...
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THEI N F L U E S C E

OF

1

USSITUR.lTIOS

SUBSTITUENT U P O S

XI-HYDROCARBON

IS THE

THE CHOLISESTERISE I X H I B I T I O N

(Ijo=tSE) OF X',S-DIETHYLSIPECOTAMIDES~

TABLE I1 THEIKFLUENCE O F UNSATURITIOS rs THE HYDROCARBOX LISKAGEUPON THE CHOLIXESTERISE INHIBITIOS (IMi SE) O F Bis [~,X-DIETHYLXIPECOTAMIDE] HYDROCARBONS

R-N HCl e o N ( c , H 5 ) z HX Is0

CIVIIl~Id

I

K

jr

.w x

SE,b 104

HX Is0

TC

CI-I,CI-I,CH?

1 0 . 1 =t O . l d 1.50 CH,=CHCH, 1 1 . 6 =t 0 . 1 1 .20 111 CI-T=CCHB ... 0.90 a Theie derivatives may also be named as 3-(N,X-diethylcarbamoy1)piperidines. Standard error calculations are based on the method of G . JV. Siledecor and \V. G. Cochran ((%atistical hIet,hods," 5th ed, Iowa State College Press, Ames, Iowa, 1956, pp 12-45) and utilize data from two to five independent determinations. Hansch's values21 (0.50 for CHI and CH?, 0.70 for CH2=CH, and 0.40 for HC-C) are additive t o give the substituent constants ( T ) listed: larger T values may be considered to represent more lipophilic moieties. The biochemical evaliiation of this compound has been previously reported.' e Inhibition not significant a t 1 X .If.

I1

phobic ratio usually enhances inhibitor effectiveness.14al 9 I n this study, special emphasis has been directed toward elucidating characteristics affecting interactions in the region of the anionic site. All of our derivativeo poqsess a positive nitrogen substituted with a hydrocarbon function incorporating varying degrees of unsaturation and structural rigidity. The effect on inhibition induced in compounds I1 and I11 (Table I) by unsaturatiori is rather unusual. Using the S1-propyl analog (I) for comparison purposes, we see that the introduction of a double bond (11) causes no appreciable activity change while insertion of a triple bond (111) is accompanied by a considerable loss in activity. Two factors, electronic and lipophilic, may be considered in regards to this change in activity. Should an electronic factor1$ be involved here, one might expect interactions of the T electrons (1) with the positively charged nitrogenzoarid ( 2 ) with the negatively charged anionic site.*O The probable significance of lipophilic properties may be inferred if one uses Hansrh's T valuesz1 (Table I) as a basis for roniparing compounds I, 11, and 111, respectively. These T values represent a decrease in lipophilic character and, therefore, one would expect a corresponding decrease in hydrophobic binding to the enzyme. However, as the lipophilic properties decrease, the electronic factor appears to become more important and even dominant in the S1-propargyl analog (111). Here, both factors may contribute to the decrease in binding ciiergy and provide an explanation for its lessened inhibitory activity. 111light of the finding of Coleman and Eleys arid Long :tiid Schueler,'O as well as our own result^,^ a study of a *erie.: of bis(S,S-diethylnipecotamide) hydrocarbons (Table 11) appeared attractive. These will be considered first with respect to the K1-alkyl, SI-alkenyl, and S1-alkynyl derivatives (IV-VIII) arid secondly with respect to the SI-xylylene analogs (IX-XI). ( l Y ) \V. P. Purcell, J . G . I(easley, R . P. Quintana, and .J. .i. Singer, .7. . l r ~ /Ciiern., . 9 , 29; (1Y66). (20) 11. .J. Yrnitli a n d H. \\illiarns, J . Tiieoret. B i d . , 11, lii (1Y66j. (21) C. Hansch. A. R . Steward, and J. Iwasa. J . .Wed. Chem., 8 , 868 (1962).

Coinwi Iv \

\I T I1

TI11 IY

X SI

HX HBr HHr HC1 HC1 HC1 HUT HC1 HEr

A -CH?CHLH&H2-CH,CH=CHCHr(czsj -CHCH=CHCH2-(transj -C H K = C C H r -CH&aCCaCCHr O- ( C H2) 2C6H4 m-(C Ha) 2CaH4 p-(CHdzC6H4

i SE,a 104

xx

4.20i 0 . 1 i b 3.2ii0.17 5.80 4Z 0 . 0 1 3 . 4 3 0.01

. . .c

0 . 6 7 4Z 0 . 0 5 1.47 i 0 . 0 1 2 . 1 8 i 0.09

See Table I, footiioie a. The biocheniit-a1 evaluation of thiq compound ha\ been previously r e p ~ r t e d . c~ Inhibition was 40Cr;. a t 1 X l O - 3 M . a

A different spectrum of activities is found for derivatives IT-VIII. Here, the effect of a single double bond may be related to the geometric configuration with the cis derivative (T-) being more active than the saturated analog (IT) and the trans derivative (TI) less active. -4further increase in unsaturation, to the triple bond level, yields a product (T'II) with essentially the same activity as the cis form (T). This result is in striking contrast to the monosubstituted series (Table I) where the change from single to double bond (I +- 11) produced no significant change in activity while the change from double to triple bond (I1.-t 111) was accompanied by a sharp decrease in activity. I n the his series, however, the insertion of a second triple bond (YIII) does induce a noticeable loss in inhibitory potency. It is possible that in the bis series, the second S,S-diethylnipecotamide function may anchor the molecule to the enzyme surface by means of ion-induced dipole forces, as suggested by Coleman and Eley* for their diquaternary compounds, and that the rigidity of the hydrocarbon linkage may affect the extent of such nonspecific binding. The stereochemistry of the inhibitor moiety, therefore, could direct the conformational perturbatiori of the enzyme surface as suggested by Belleau18" and, consequently, control the degree of inhibition. The rigidity of the hydrocarbon linkage in TI11 may also indicate the influence of a spatial factor (e.g., nitrogennitrogen distance) in binding of inhibitor to enzyme. Thomas and lIarlow14ahave shown that trimethylbenzylammonium iodide is a fair XChE inhibitor. This prompted us to try an aralkyl group as a source of structural rigidity and unsaturation in our bis-substituted inhibitors and led to the synthesis16 and biochemical evaluation of compounds IX-XI (Table 11). The order of decreasing inhibitory activity fouiid for these products was odho (IX) > meta (X) > para (SI). Differences in the stereochemistry and lipophilic characteristics of these molecules would be signifirant and, we believe, niore influential in determining inhibitory properties than the electronic and ionic- volume factors which should be siniilar for each derivative. QuintanaZ2has found appreciable cliff erence- in the benzene/ water partition coefficients of nipecotamide and isonipecot:miitlc (~-~~iperitliriec:~rl~os:iiiiicle) :iii:ilogs. The former was niore lipophilic and niore potent as a ChE (22) K

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