3775
J . Med. Chem. 1994,37,3775-3788
Construction of a Molecular Shape Analysis-Three-Dimensional Quantitative Structure-Analysis Relationship for an Analog Series of Pyridobenzodiazepinone Inhibitors of Muscarinic 2 and 3 Receptors Benjamin J. Burke,? William J. Dunn, 111, and A. J. Hopfinger* Laboratory of Molecular Modeling and Design, Department of Medicinal Chemistry and Pharmacognosy, M I C 781, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612-7231 Received April 29, 1994@
A generalized three-dimensional (3D) quantitative structure-property relationship (QSPR) formalism, based upon molecular shape analysis (MSA), has been applied to a n analog series of pyridobenzodiazepinone inhibitors of muscarinic 2 (M2) and 3 (M3) receptors. The fundamental goal of this application is to establish MSA-3D-QSARs (P = A = inhibition activity) t h a t are based upon identifying the active conformations of these flexible analogs. The repetitive use of partial least squares (PLS) analysis permits the construction of the MSA3D-QSARs. In addition to molecular shape, the identification of the properties of a lipophilic binding site and specific nonallowed steric receptor sites govern the MSA-3D-QSARs. The M2 and M3 QSARs suggest receptor subtype specificity might be realized by targeting upon a specific nonallowed steric receptor site. One conformation, common to both M2 and M3 receptors, emerges as dominant in the optimum MSA-3D-QSARs. However, other similar conformations are also found to yield meaningful MSA-3D-QSARs. Introduction
In the previous paper1 we describe a general formalism to construct MSA-3D-QSPRs for a set of flexible molecules {Mu} using multiple trial molecular alignments. In the case of the relative physicochemical feature representation, three classes of feature tensors can be defined as the basis for the QSPR: V,,,(s,a,P) is the intrinsic steric molecular shape (SMS) tensor where s refers t o the set of steric shape measures, a the set of conformations, and p the set of alignments considered in the analysis of {Mu}. Compound v is the reference compound1 and u is any member of the data set. F,,,(p,rj,k,l,a,P) is the molecular field (MF) tensor where p are the set of probes used to generate the molecular field features2 and the rj,k,l are the spatial positions at which the potential field is evaluated for each p . H,,,(a,p) is the tensor which contains all the remaining physicochemical features which may, or may not, depend on a and/or P. These three tensors can be combined to yield the VFH tensor which is related to the property measures {P,} = P, by
Possible substitutions:
m=0.1,2 p=o, I ,2
n=1,2 RI.R2in Table I
“CENTRAL RING”
J-J
‘Y”
H-N+-
I R2
Ri
“SIDE-CHAIN”
Figure 1. Core structure of the pyridobenzodiazepinone analog series. The structure is divided into three portions. The tricyclic portion of the molecule is referred to as the “top”,the middle portion is referred to as the “central ring“, and the lower portion as the “side chain” portion of the molecule.
for which both cardiac and ileal inhibitory activities have been m e a ~ u r e d .In ~ this MSA-3D-QSAR application the alignment is restricted to one choice and p , = Tu,, @ [Vu,v(~,~,B),Fu,v(~,~j,~,l,~,P),~,,(a,B)l (1) molecular field features are not employed. Consequently, eq 1 reduces to where Tu,, is the transformation tensor that establishes the specific relationship between {Pu}and VFH. The p , = Tu,, @ [V,,”(s,a,Po),IZ,,(a,Bo~l (2) current approach to determining Tu,,is the repeated application of partial least squares (PLS) regre~sion.~ where Po indicates that only one choice in molecular alignment is being considered. In essence, this applicaEquation 1 can be decomposed into a variety of tion focuses upon establishing the optimum relationsubmodel QSPRs. In fact, all popular methods of QSPR ships between the P, and conformational features. analysis are contained within the framework of eq 1.l In this paper we apply eq 1 to the MSA-3D-QSAR Methods analysis of an analog series of muscarinic antagonists ~
~~
* Author to whom correspondence should be addressed.
Current address: Agouron Pharmaceuticals, Inc., 3565 General Atomics Court, San Diego, CA 92121. Abstract published in Advance ACS Abstracts, September 15,1994. @
1. SAR Database. Engel et aL4 report the cardiac (M2) and ileal inhibitory (M3) activities for an analog series of 26 muscarinic antagonists. The core structure of this series is given in Figure 1. Nineteen of the 26 compounds from the original data base4 were selected for MSA-3D-QSAR analysis
0 1994 American Chemical Society
Burke et al.
3776 Journal of Medicinal Chemistry, 1994, Vol. 37, No. 22
Table 1. Some of the Substituted Tricyclic PyridobenzodiazepinonesUsed in the 3D-QSAR Analysis and Their Binding Affinities to Cardiac (M2) and Glandular (M3) Tissue Given as IC50 (nMP
1 &N-
2
ICmnM Sele#ivicy -M2
R
No.
M3
MyM3
5000 >loo00
\
f WN\
140
>2
4
5
f y \-
R
Selectivity MZm(3
M2
M3
100
200 2.0
600 3000
6OOO 42.9
i .,’ 220 W / p [330
3
IC*aM
No.
5
2.7
60
150 2.5
1000 3.0
30
70 2.3
600
1500 6OOO
200
3.3
k.,? 170
300
1.8
560 1500 2.7
7 ‘ N L ~ Z 800
4OOO
5
600 1500 2.5
2000
13
>I000 4Ooo
