PARTITIOX COEFFICIENTS A N D CHOLINESTERASE IKHIBITIOK
N a y 1966
297
TABLEV CHOLINESTERASE IKHIBITORY PROPERTIES O F 1-DECYL-3-[ (N-ALKYL)- AKD 1-DECYL-3-[( N,N-DIBLKYL)SUBSTITUTED CARBAMOYL]PIPERIDINES
: 0.26
0.25 0.24
g 0.21
NRiRz
0
.$ 0.20
z
0.19
0.18
c
0.14 0.13
1
Iso, Af
x
1065
6 . 23b NHCH3 3.4gb 1.37b NHCzHj N(CH3)z 2.17b N( C2&)2 0.53" N(CJ%)z 0. 105d a Molarity of inhibitor effecting 507, inhibition. See ref 7b. See ref 7a. J. G. Beasley, unpublished data. 2"
2
3
41
5
4
x
6
105.
Figure 1.-Net charge at the amide nitrogen atom of l-decyl3-[(alkyl)- and 1-decyl-3-[( N,N-dialky1)-substituted carbamoyl]piperidines us. the coiresponding cholinesterase inhibition.
Acknowledgment.-The author wishes to thank Dr. Charles W. Sheppard for his kind assistance in computer programming and Miss Joan S. Hendrix for her help in operating the IBM 1620 computer. ,41so, we are grateful to the Xational Science Foundation and the Walter Reed Army Institute of Research for their support of this research. This paper is contribution Xo. 42 from the Army Research Program on Malaria.
Application of Partition Coefficients, Electric Moments, Electronic Structures, and Free-Energy Relationships to the Interpretation of Cholinesterase Inhibition1 WILLIAMP. PURCELL, JAMES G. BEASLEY, RONALD P. QUINTANA,
bND
JUDITH A. SINGER
Department of Pharmaceutical and ,Vedicinal Chemistry, University of Tennessee College of Pharmacy, Memphis, Tennessee 58103 Received December 14, 1966 Cholinesterase inhibition of some N-alkyl-substituted amides is interpreted in the light of their partition coefficients, electric dipole moments, electronic structures calculated from the Huckel molecular orbital method, and free-energy relationships. At least 7-57, of the observed cholinesterase inhibition can be accounted for from a linear relationship between log 160 and log (partition coefficient). The activities of seven mono(carbamoy1piperidino)decanes are explained in terms of electronic, stereochemical, and hydrogen-bonding factors. The inhibitory properties of several mono- and bis[3-(N,N-diethylcarbamoyl)piperidino]alkanea are discussed from considerations of the smooth curves obtained from plotting l/ZjO against n, the number of carbon atoms in the alkyl chain. I t is believed that the mono derivatives have competing electronic and hydrophobic factors which contribute to the activity, while the inhibition of the bis compounds can be approximated nicely from the Bn C. Linear free-energy relationships indicate that the inhibitors under parabolic equation, l/Z, = An2 study have similar binding modes. A model for the inhibitor-enzyme complex is proposed which has points of attachment (1)a t the anionic site between the carboxyl group of the enzyme and the positively charged quaternary ring nitrogen of the inhibitor, and (2) a t the esteratic site in the form of a quasi-ring formed from association of (a) the serine hydroxyl oxygen of the enzyme with the amide nitrogen of the inhibitor, and ( b ) the serine hydroxyl hydrogen of the enzyme with the amide oxygen.
+
+
The inhibitory effect upon isolated human plasma pseudocholinesterase (acylcholine acylhydrolase, EC 3.1.1.8) systems produced by series of substituted arylalkylaminopropionamidesz~3and of piperidinecarboxamide derivatives4s5 has been studied extensively.
I n continuing investigations designed to elucidate structureactivity relat,ionships in these series, we have (1) measured dielectric properties,6--s (2) calculated electronic struct'ures,g (3) applied regression analyses1O to the structure-activity data, (4) evaluated surface-
(1) This research is being supported b y the National Science Foundation (GB-2381/B-15989). Computer facilities were provided through U. S. Public Health Service Grant HE-09495. (2) A. Lasslo, P. D. Waller, A. L. hleyer, and B. V. R a m a Sastry, J . M e d . PhaTm. Chem., 2, 617 (1960). (3) -1.Lasslo, P. D. Waller. a n d G. J. Epperson, ibid., 6, 26 (1963). (4) A. Lasslo, J. G. Beasley. G. G . Nelms, and G. J . Epperson, ibid., 6, 811 (1963).
(5) J. G. Beasley, R. P. Quintana, and G. G. Nelms, ibid., 7 , 698 (1964). (6) W.P. Purcell, J . P h y s . Chem., 68, 2666 (1964). (7) W.P. Purcell and J. A. Singer, ibid., 69, 691 (1965). (8) W. P. Puroell, J. G. Beasley, and R . P. Quintana, B i o c h i m . B i o p h y s . Acta, 88, 233 (1964). (9) W.P. Purcell, J . Med. Chem., 9, 294 (1966). (10) W.P. Purcell, B i o c h i m . B i o p h y s . Acta. 1011, 201 (1965).
ive pi,operties,11si2:mcl ( 3 ) iiieasurctl iiartition cmffic~itritst3 of some of our c:holiiiesterase inhibitors. 111 v i m of tlic increased eni1)hasis OII physicochcniit*:rl cdoii,4derations in examining the behavior of syrit Iic.tic* entities in biological systenis,i4-16we have a t ~wil)teclto ai)l)ro:ich our experiniciit:Ll observntions with :il)l)roi)riate mathematical iiitcrl)retations aritl rorrelnt ions. \Ye have found (1) a linear relationship between log 1:" :itid log 1)artition c.oefficierit which accounts for at) 1c:ist 7.i%, of the observed activity (i.e., the maximum tlcviatiori b e t w e n observed 1:"and calculated Iiois 2pj?A); ( 2 ) a i)arabolic relationship between 1/I30 aiid H , the iiuiiiber of carbon atonis in the alkyl chain
water partition roefficieiits of' a seriw of nioiio(vxr-1 log-log 1)lot (I'igure I ) hamoylpipei~idi~i~~)decaiies. of tliesc in-o paramettw is liiiear, i.e., t hc proiwtiew n hci apl)rosim:itetl mt,hcr closely by ecl 1
:irt
1:
~
(1
(,[J>n
1
n-hcrc: c is thc antilog of t h e 1 ~ ~ : i s t - q w ~intrrc.cl)t rw 01' log 15,cs. log P , P is tlic partition coefficient, Litit1 i i i i: the slope of thc least-squarcs line (I'igure 1). Table I1 gives t h r ohscrvcd (T:iblc 1) :iiitl c ~ a l c u l a t ( ~ ~ jeq 1) J 3 " v:tlucs, atid :11>o 1 lI(3 valL1cY of 7i ( ~ d ( ~ l l l : L i ( T l froni Haiiscli's tlefinitio~ili x
=
log I ' s
-
lug
1'11
where 1's is the ~~nrtitioii coeffiric~itof P I T is that of the parent conipoiuicl.
(2, ;itlwivativc. : i i i t l
Cholinesterase Inhibition and Polarity.- - -111I'igur~~ 2a we ha\Te plotted the inhibitiori agaiiist t1w aiiiitlc of several bis[3-(S,S-diethylcarbamoyl)piperidirio]group nio1nent1~from the t l a t n i i i Table I . I r i t l i v :[Iliaties : : i d ( 3 ) free-energy relationships that indicate :djacent figure (I'igurv 2b) thc, itihibitioii is I)loftetl siniilar niodcs of molecular binding t o eoniiiion enzynic (using t h e saiiic sc:ilc :I< I'igurcx .)a) :igajtiyt ~ h not t ~ sites for our inhibitors. Also we consider (1) electronic electronic charge at the :imide nitrogen :ttoni. structure (:is determiried froni electric dipole nionierit Cholinesterase Inhibition and Alkyl Chain Length. ni(xsurenimt s and Huckel niolecu1:ir orbital (HJIO) I'reviously,~n-c' rc1)ortetl grai)hic relntiolishi~,sbet w c ~ ~ i i c d ~ w l niotih), t ( 2 ) stereoc~lieniical factors, and ( 3 ) log I j 0 and log n , tlie iiuniber of' r n r b o ~atoilis ~ in tllv hydrogen-bondiri~Iiossibilities in the interpretation of :ilkyl chain, for hcvernl iiioiio- and bis[3-(S,S-dieth?.lt l i e inhihit~ion of some iiiotio(carbamoylpiperic~iri0)- c~arbanioy1)~ii~~ericliiio J:illciries. Upon closer cx:miii:ider:\lleS. tion of the data. we found :i rnt,her smooth curve when Development and Derivation of Relationships. Cho1/Ib0 was plotted ag:tinst 11, t)he number of carbon atonis linesterase Inhibition a s a Function of Partition Coin t h e alkyl chaiii. In fact, for the bis derivatives, tlie efficient.----Table I gives t lic act ivities and b e i m m 1)ointsfit the equation for a ~ ~ a r a b ofairly la i\-eIl; T:ible ( I 1) It. 1'. Quintana, J . Z'harm. Sei.. 63, 1221 [ l W 4 j . ( 1 2 ) R . 1'. Quintana, i b z d . , 54, ,57:3 (19tG). (13) Et. 1'. Quintana, &id., 5 4 , 462 (1963). (1.1) \V. U. XI. Paton, I'TOC. Roy. SOC.(London), B154, '21 ( I W I ) , rikns s n d .-I.11. Simonis, .I. I'hurm. Phurmacol.. 16, 1 S 7 (lU64); 11.5) 1,:. J. .iriens a n d A . M . Sirnonis, ibid., 16, 289 (1964). (16) 13. Helleau, J . M e d . Chem., 7 , 776 (1964).
(17) T. I.'ujita.
