662 .Journal
of Medicinal Chemistry, 1975,
Vol. 18, No. 7
Pharmacodyn. Ther., 186 (1957). (11) H. W. Kosterlitz and A. J. Watt, Br. J . Pharmacol. Chemo-
ther., 23,266 (1963). (12) B. M. Cox and M. Weinstock, Er. J . Pharmacol. Chemother., 27,81 (1966). (1 3 ) Dr. William Forrest, private communication, Department of Anesthesia, Stanford Medical Center. (14) T. D. Pernine, L. Atwell, I. B. Tice, A. E. Jacobson, and E. L. May, J . Pharm. Sci., 61 (No. l ) , 86 (1972). (15) R. I. Taber, Adu. Biochem. Psychopharmacol., 8,191 (1974). (16) N. B. Eddy, H. Halbach, and 0. J. Braenden, Bull. W . H . 0.. 14,353 (1956). (17) J. Pearl, H. Stander, and D. B. KcKean, J . Pharmacol. E r p . Ther., 167,9 (1969). (18) J . Weijland and A. E. Erickson, J . A m . Chem. Soc., 64, 868 (1942). (19) K. Unna, J . Pharmacol. E r p . Ther., 79,27 (1943). (20) W. L. McCawley, E. R. Hart, and D. F. March, J . A m . Chem. Soc., 63,314 (1941). (21) A. R. Wikler, L. C. Fraser, and H. Isbell, Fed. Proc., Fed. A m .
Farnell, Richards, Ganellin Soc. E r p . Bioi., 11,402 (1952). ( 2 2 ) G. W. Gorodetzky, Adu. Riochem. Psychopharmacol., 8 , 191
(1974). (23) A. E. Takemori, H. J. Kupferberg, and ,J, W. Miller, J . Pharmacol. E r p . Ther., 169 (No. l ) ,39 (1969). (24) B. M. Cox and M. Weinstock, Rr. .I Pharmacol.. 22, 289 ( 1964). (25) S. Diner, J. P. Malrieu, F. Jordam, and M. Gilliert, Th(vir. Chim. Acta, 15,100 (1969), and references cited therein. (26) J. Pople and D. Beveridge, “Approximate Molecular Orbital Theory”, McGraw-Hill, New York, N.Y., 1970. (277) L. Gylbert, Acta Crptallogr., Sect. R, 29, 1630 (1973). (28) “Tables of Interatomic Distances and Configuration in Molecules and Ions”, Chem. Soc., Spec. Publ., No. 11 (1958). (29) J. J . Kaufman and E. Kerman, Ini J . Quantum Chcm., 6 , :119 (1972). (30) J. J. Kaufman and E. Kerman, Int. J . Quantum (’hem., Symp., 8,289-313 (1974). (31) Robert Willette, NIH, private communication. (32) G. Loew and D. Berkowitz, unpublished results.
Conformation of Histamine Derivatives. 5. MoIecular Orbital Calculation of the HI-Receptor “Essential” Conformation of Histaminel L. Fzrnell, W. G. Richards,* Physical Chemistry Laboratory, Oxford University, Oxford OX1 3QZ, England
and C . R. Ganellin’ T h e Research Institute, S m i t h Kline & French Laboratories Ltd., Welwyn Garden City, Hertfordshire, England. Receiiled February 7, 1975
Conformational energies of histamine and 4-methylhistamine monocations are calculated using the EHT molecular orbital procedure; the results are expressed as potential energy surfaces in which bond rotations (01for ring-Cd, O2 for C&,) are measured along the axes, and energy variation is indicated by contours. Using the classical Boltzmann partition function and Simpson’s rule for normalization, corresponding probability surfaces are generated which take account of the potential surface entropy. Comparing the two surfaces provides regions which are within a given probability contour of histamine but outside this contour for 4-methylhistamine. Thus, at the 99% probability level, three conformational regions defined by the bond rotation angles are indicated as possible “HI-essential” conformations of histamine: viz. trans (81 = 290-330°, 82 = 150-210°) aod gauche (8, = 260-280°, 8 2 = 30-90’ and 81 = 290-320°, HZ = 270-320’). This procedure provides a quantitative basis for comparison with other histamine derivatives and may have a general value for studying relationships between conformation and biological activity of closely related small molecules Two types of histamine receptor, H1 and Hz, have recently been characterized by using selective histamine-like stimulants (agonists) and selective histamine-blocking agents (antagonists).2 A selective agonist of considerable interest is 4-methylhistamine [4-methyl-5-(2-aminoethyl)imidazole]; it has about half t h e activity of histamine at H2 receptors but only l/Sooth of t h e activity at HI receptors. This marked effect of a 4-methyl substituent on HI-receptor agonist activity poses an intriguing medicinal chemical problem and provides a n opportunity to identify chemical properties of histamine likely to be involved in HI-receptor stimulation. We have previously shown3 by EHT calculation that 4methylhistamine may differ from histamine in its conformational properties. T h e calculations suggested that t h e methyl substituent influences the orientation of t h e imidazole ring with respect t o the side chain and introduces a measure of rigidity through restricting ring rotation. We d o not know whether these changes account for the observed biological difference but we can explore this as a possibility. If 4-methylhistamine is ineffective as a n HI-receptor stimulant because of restricted rotation or of its inability to assume a necessary conformation then we can define for
histamine the “HI-essential” conformations, i.e., conformations essential to drug activity which have to be adopted by drug molecules a t some stage during productive interaction a t the HI-receptor site. T o do this we must find those conformations which are accessible t o histamine but inaccessib l e to 4-methylhistamine. We have previously argued this in a qualitative manner;4 in the present paper we make i t more quantitative. Calculations were performed on histamine and 4-methylhistamine monocations in their N3-H (N7-H)6 tautomeric forms (Figure 1) using the nomenclature and geometry previously given5 As before, the conformation is described by t h e two torsion angles O1 and 8 2 which, respectively, represent rotation of t h e imidazole ring about the bond CS-C,~, and rotation within t h e side chain about the bond CFC,,. T h e symmetrical ammonium group was held in a staggered position ( 8 3 = 60’) with respect t o C,. In 4-methylhistamine t h e symmetrical methyl substituent was rotated to minimize the energy for given values of 81 and 82; for most of the surface t h e orientation 84 = 120’ is most favorable, b u t as 81 approaches O’, O4 tends toward 7 5 O , and similarly as 81 approaches 360°, 84 tends toward 165’. T h e total internal molecular energies were calculated
Journal of Medicinal Chemistry, 1975,Vol. 18,No.7 663
Conformation of Histamine Derivatives
'H
H N-C
H3C-C4,5
I
li"
4
04
H
H
I
H
82
(C)
Figure 1. 4-Methylhistamine monocation (N3-H tautomer) showing (a) atom numbering and torsion angles; (b) torsion angle 81 viewed along CpC5 bond, looking from Cg to Cg; (c) torsion angle 8 2 viewed along C,-Cg bond, looking from C, to Cg; and (d) torsion angle 84 viewed along CH3-C4 bond, looking from CH3 to Cq.
-
0 -
240
Table I. Energies by E H T of Minimum Energy Conformations for Histamine and 4-Methylhistamine Monocations
Molecule
t-
300
01, deg
0 2 , deg
Total energy, eV
90 120 120 240 240 270 90
60 180 3 00 60 180 300 60 300 180 60 300
-7 9 9.5 5 6 -799.599" -799.584 -799.584 -799.599" -799.556 -903.668 -903.678 -903.722a -903.678 -9 03.6 6 8
-
180 120-
Histamine
4 -Methylhistamine
150 180 2 10 270
"Indicates global minima, using extended Huckel theory ( E H T ) taking 15' increments in each angle over the whole geometrical range 0360'. T h e results are expressed as a potential energy surface where the variation in the angles is measured along the axes and the variation in energy is indicated by appropriate contours (Figure 2). Stable conformations correspond t o minima on these surfaces. T h e values of the minima found for the two molecules are given in Table I. T h e justification for using the E H T method is in the measure of agreement between the predictions of conformer previously population ratios, for histamine and its methyl derivatives, and the values experimentally determined by nuclear magnetic resonance spectroscopy (NMR). This agreement is not obtained when more sophisticated molecular orbital methods such as CNDO or PCILO are employed (see ref 8 for a discussion of this). Furthermore, it must be stressed t h a t in the present paper comparisons are only made between two chemically similar molecules. By using hista-
60
82
Figure 2. Conformational energy maps of (a) histamine and (b) 4methylhistamine monocations. The internal energies are indicated by contours spaced by 0.05 eV relative to the global minima (marked by +).
mine for chemical and pharmacological reference and examining 4-methylhistamine for differences, one can avoid many of the problems associated with assessing the validity of absolute data. For histamine (Figure 2a) there are three main potential energy troughs corresponding t o three stable conformations (one trans and two enantiomerically related gauche forms) each of which has two deep wells. They are defined by the energy contours and enclose the regions of conformational space given by the values of 81 and 82 corresponding t o the boundaries. At the contour 0.1 eV above the global minima (marked by +) the boundaries enclose the ranges 81 = 50-275', 82 = 40-90'; 81 = 40-320°, 8 2 = 150210'; and 81 = 80-310', 82 = 270-315'. Similarly, 4-methylhistamine (Figure 2b) has three main potential energy troughs corresponding t o three stable conformations. By comparison with those of histamine, however, the energy troughs have steeper sides. At the 0.1-eV contour the
664 Journal ojhfedicinai Chemrstr!,, 1975, Vol 18, N o 7
FurnPl1, Richards, Gunellin
Table 11. "H1-Essential" Conformations 01 Histamine
3 6 0 _Defined by the 0.1-eV Energy Contour5
-300
CD
240
*
-
1,
der
'1.
255-275 290-320 285-310
-
180 -
I) e b ( 1'11111t 1 I 1
dec
4040 150-210 280-315
G'Luc hi' T I' X I i c;,lLIC
Table 111. Conformational Regions Defined at Different Energy Contours for Histamine and 4-Methylhistamine
I
~-_______
~
IZO-
Energy Histamine 'olltour,-p eV f;*, deg t ' ? . deg
60 -
1 Od
he
'
60 '
I
I20
'
180 I
I
240
I
82
300 '
I
'
0.05
360
Figure 3. Superimposed 0.1 -eY energy contour of histamine (unhrokrn line) and l-methylhistamine (dotted line) to reveal the "Hi-risrntial" ctinforniational regions. indicated hy t h e hatched
0.1
area-. 0.2 houndaries enclose the ranges 01 = 70-255", 02 = 45-80'; 01 = 7OL29O0: H i = ltiS-20t5"; 0 , = 10t5-28,5O, 8 2 = 280-310". Thus. t'or 4methylhist,amine the range of conformations accessible when using the 0.1-eV energy contour as a limit is narrower than it is for histamine. Beyond this range are conformations inaccessible at the level of this choice of lirriit . Superimposing the respective 0.1-eV energy contours from the maps of the two molecules shows the regions acible to histamine but inaccessible to 4-methylhistamine ((4'. the hatched areas in Figure 3); those areas within the 0.1 -eV energy contour of histamine, which lie outside the corresponding contour for 4-methylhistamine, represent possihle " H I -essential" conformations, At this level, six areas are defined which, through molecular symmetry, correspond to three different conformational regions (see 'I'ahle 11). T h e selection of0.1 e\' as the critical energy contour is arhitrary, ho.ive\.er. Different conformational ranges are available at other energies. A much lower contour. for example. 0.05 eY. would restrict the accessible conformations t o smaller ranges of 11 (see Table 111): conversely, a higher contour isrich as 0.2 e\') ext,ends the range. A I)et ter definition can be provided in terms of probabilities, i.e.. relative conformational populations. Either the probahility of a given conformation or the range of conformations permitted b!- a given probability may he calculatid. T h e latter is more useful for the present purpose. I t is insufficient, however. to obtain the probabilities by simply cwmparing the internal energies since this presumes t h a t the internal differences are equivalent to free-energy differences; this can only he true if entropy changes are unimportant. (hisideration of a surface reveals a danger in using internal energy differences: t h e relative populations o f two valleys in a potential surface depend not only on their depths but also on their curvatures. A broad valley indicates a higher entropy than a narrow valley and so a sufficiently broad valley may have a higher population than a deeper hut narrower valley.' .Associated with each point ( i l L , i ! , ) on the surface is a prohability defined as %,, = e-', ik7 where ti, is the energy at the point (1, = 0 , . 0, = fi,, 1: is the Boltzmann constant.
210-260 75-135 70-290 100-150 225-285 50-275 40-320 80-310 25-290 0-360 7 0 --325
5040 60-80 165 -195 280-310 280-300 40-90 150 -2 10 270-315 35-105 135-2 2 5 255-325
----
.
4 -Methylli is t a ni ine ~~
ijl.
deg
1 1 ~ .
deg
80-280 120-170
165-195 295-300
70-255 70-290 105-285 70-260 65 295 100-290
45-80 155-205 280-310 40 100 140-220 260-320
1)escrii)tion
Tr,ln> Gkiiic 11~'
C,LU
