The computational design of amidines as H2-receptor agonists. The reduction of the amidine group basicity in N-methylformamidine analogues

Journal of Molecular Structure (Theochem) , 219 (1993) 1S-21 Elsevier Science Publishers B.V., Amsterdam

15

The computational design of amidines as Hz-receptor agonists. The reduction of the amidine group basicity in N-methylformamidine analogues* Michael

Sabio and Sid Topiol

Molecular Modeling, Preclinical Research, Sandoz Research Institute, East Hanover, NJ 07936 (USA) (Received 14 November

1991; in final form 2 June 1992)

Abstract In a previous study, we explored the use of an amidine group as a replacement of histamine’s imidazole ring in the context of a previously proposed model of recognition and activation at the H, receptor. We concluded that the unsubstituted acyclic formamidine group, as opposed to the amine group, in N-(3-aminopropyl)formamidine (NAPF) would be preferentially protonated, a condition that is contrary to the requirements of the HZ-receptor model; however, NAPF (with the primary site of protonation arbitrarily assumed to be the amino group) was shown to be useful in testing the model. In the present study, we computationally examine analogues of N-methylformamidine (in various isomeric and tautomeric forms) as a model of NAPF to determine which modifications of the amidine group are necessary to lower its basicity (as measured by proton affinities). These derivatives are substituted at an amidine carbon atom or nitrogen position (preserving the possibility of tautomerism) with functional groups of varying electron-withdrawing strengths. At the Hartree-Fock and second-order Merller-Plesset levels of theory, the calculations reveal that some of the analogues possess a comparable or lower proton affinity than that of a model of NAPF’s amino alkyl side-chain (i.e. methylamine) and, at the same time, exist to a significant degree as the Nl-H tautomer in the neutral state; both of these attributes are required by the proposed HZ-receptor model. Thus it seems possible to design such amidines as HZ-receptor agonists. We show that the proton affinities are correlated with the electronic effects of the substituents and with the energy difference between the Nl-H and N3-H tautomers. Additional calculations on amine-protonated.analogues of the compounds studied herein are necessary to determine whether the protonated form exists at a significant level as the N3-H tautomer, as required by the proposed model.

Introduction In our previous computational study [l] of the minimal requirements for HZ-receptor agonists, we explored the use of an amidine group as a replacement of histamine’s imidazole ring in the context of a previously proposed model [2]. In the model, the Correspondence to: S. Topiol, Molecular Modeling, Preclinical Research, Sandoz Research Institute, East Hanover, NJ 07936, USA. *The majority of this work was conducted in the Department of Medicinal Chemistry, Berlex Laboratories, Inc., Cedar Knolls, NJ 07927, USA.

activation of the HZ-receptor by histamine is initiated by a charge relay resulting from a shift in proton tautomeric preference that involves the two imidazole nitrogen atoms. The requirement of a shift in tautomeric preference in this model, based on structure-activity relationships of histamine analogues [3], is thought to be induced by the neutralization of the side-chain ammonium group (Fig. 1 (top)). Thus, histamine, as the monocation, in the N3-H tautomeric form, is neutralized by interaction of the cationic side-chain with a negative region of the receptor, thereby inducing a shift in tautomeric preference to the Nl-H form. We note

0166-1280/93/$06.00 0 1993 Elsevier Science Publishers B.V. All rights reserved.

M. Sabio and S. Topiol/J. Mol. Strut.

16

(Theochem)

279 (1993)

15-27

Histamine

iI 2 Yw 1.H

. N

31

N,-H Tautomer

Nl-H Tautomer

<

N-Methyl Formamidine

Analogy

&-H

(R, = H, CN;

Tautomer

R2 = H, CN, CF,, CH2CH3)

&-H Tautomer

Cation

B IsomerS Trans Methyl

Yl

YH3

,N*3*N.

Y

&,

H

R,

Cis Methyl

Tram Methyl

FH3 /N, &,

Y

N.

H

R2

Cis Methyl R2

FH3 F

h-N, lZCNJjH

R2

-N f&

R,-N pEJ

__ )_ r‘ +

‘H

CH3

N’ ‘H

M. Sabio and S. TopiollJ. Mol. Struck

that

the Nl-H

tautomer

stable neutral finding may

may

effects.

tomeric preference (upon neutralization) of the model

However,

a shift

that is less sensitive

chemical calculations,

ab

initio

and

i.e. N-(3-aminopropyl)formato

determine

the

tautomeric

preference as a function of the protonation the aminopropyl group. We noted that

state of because

the amidine group is expected [5] to be more basic than the amino group, the amidine portion would

interact

with

the

neutralizing

region

arbitrarily ation)

NAPF

chosen

could

serve as a useful

of the

the amino

as the primary

better understand activation at the terms

(with

the minimal H, receptor.

computational

group

site of proton-

model

to help one

requirements In addition, results,

the

of in

depro-

tonation of the cationic species is expected to be similar to the neutralization of the cation with a suitable model of a negative region on the receptor

PIWe concluded

[l] that the minimal

(see Fig. 1) as models

that are expected

of NAPF

analogues

to fulfill the requirements

of the

proposed model. If appropriate MFA analogues are found, i.e. those in which the basicity of the amidine moiety is less than (or comparable to) that alkyl group,

the electron-withdrawing

In the previous

and present

design and test compounds features of the proposed

studies,

our aim is to

that possess the critical HZ-receptor activation

model. We may be able to provide insights into the requirements of action of known HZ-receptor agonists that may lead, for example, to the design of novel cardiovascular agents, which interest has revived [6-91.

a possibility

in

of

the H, receptor [2,4]. Therefore the amidine group could not participate in the proton-relay mechanism required by the proposed model. However, as we indicated,

(MFA)

of an amino

quantum

amidine

17

15-27

substituents of the amidine portion responsible for that effect may be incorporated into NAPF to create (presumably) a potent H, agonist.

[l] one of the

containing

groups,

(NAPF),

in tau-

to the computa-

we investigated

compounds

midine

be the more

toward the Nl-H tautomer has been used as a condition

tional approach used [ 1,2,4]. With semiempirical and

ethylamine

not

279 (1993)

form in all these studies and that this be due to the absence of detailed

environmental

smallest

(Theochem)

requirements

for activation are satisfied when the amidine replacement is made. Thus it may be possible to design such amidine H, agonists. As indicated, we needed to modify NAPF through derivatization or cyclization to reduce the basicity of the amidine group, allowing the amino group to be the primary site of protonation. To this end, in the present work we examine analogues of N-methylformamidine

Methods At the ab initio Hartree-Fock [lo] level with the use of the 4-31G*(5D) basis set (the 4-3 1G basis set [l l] augmented with a set of five d-type functions), the geometries of N-methyl formamidine (MFA) and several analogues (-H or -C-N at C2; -H, at N3; see Fig. 1) were -CF,, -C-N, or -CH,-CF, optimized with full relaxation of all geometric parameters. In addition, molecular energies of the structures derived from these geometry optimizations were calculated at the second-order MsllerPlesset (MP2) perturbation theory [12] level with the 4-31G*(5D) basis set [l l] and with the use of the frozen-core approximation. The methods for the evaluation of energies in the geometry optimizations and in the single-point calculations are referred to herein as HF and MP2 respectively. The geometry optimizations were performed for the Nl-H and N3-H tautomers and the related cations of MFA and its analogues (see Fig. 1). For analogues that contain rotatable single bonds, a

Fig. 1. Histamine is depicted in the context of a previously proposed model of the recognition and activation at the HZ-receptor (refer to the text for details); here, D and A represent a hydrogen bond donor and acceptor that are involved in the proton transfer mechanism. Below this representation are the structures of the N-methylformamidine analogues of this study. The filled lobes represent regions of high electron density. The four rows of MFA structures are arranged in decreasing similarity to histamine in terms of the geometric requirements of the proposed proton-relay process of HZ-receptor activation.

18

M. Sabio and S. Topiol/J. Mol. Strut.

conformational analysis located minima that differ from one another by the rotational state of the substituents at N3 and C2 (i.e. R, and R2, respectively, in Fig. 1; note that the nomenclature used herein is based on that which is used for histamine). In addition, because the trivalent nitrogen atoms in the Nl-H and N3-H tautomers are not necessarily planar in each structure at the level of theory used in this study, a more extensive set of structures was developed by consideration of the inversion of the pyramidal nitrogen atoms (when they are present and when the inversion would produce a second structure significantly different from the mirror image of the structure before inversion). For the comparison of proton affinities, the minimized energies of protonated and neutral methylamine (MA) were obtained (with full relaxation as in all the other calculations). All geometry optimizations were performed with the GAUSSIAN 90 system of programs [13]. Results and discussion

Presented at the top of Fig. 1 are histamine’s N3-H and Nl-H tautomeric forms as they appear in the context of the Hz-receptor activation model. In this model, histamine is present as the (sidechain) amine cation in the N3-H form (see Fig. 1; top left), before interaction with the receptor. At the receptor, the cationic side-chain interacts with a negative region of the receptor, thereby causing a change in the relative preference toward the Nl-H tautomer. This induced change in tautomeric shift is accommodated at the receptor (see Fig. 1; top right) by proton-donor (D) and proton-acceptor (A) moieties that are suitably situated. Thus, in the model, the monocation is protonated at the amine side-chain rather than at the imidazole (amidine) group. In the four rows below this depiction are the isomeric/tautomeric forms considered in this study of MFA and its analogues. The letters E (trans) and Z (cis) in the four-letter designations of Fig. 1 describe the relationship between the R, and R2 groups; T (trans) and C (cis) denote the position of R2 relative to that of the methyl group. The methyl

(Theochem)

279 (1993) 15-27

group is a model for the side-chain that, in an agonist, would contain an amino group necessary for recognition at the H, receptor. The four rows of MFA structures are arranged in decreasing similarity to histamine (top of Fig. 1) in terms of geometric requirements of the proposed proton-relay process of Hz-receptor activation (the filled lobe next to each divalent nitrogen atom is meant to represent a site of high electron density involved in the protonrelay mechanism; the “lone pair” of electrons on the nitrogen atom is thought to be delocalized, to some extent, over the conjugated system). Because of their geometric compatibility with the proposed histamine H, -receptor activation, the “ET” structures are the focus of this discussion. The MFA analogues described below have either a hydrogen atom or cyano group as R, and a hydrogen atom, trifluoromethyl group, cyano group, or a -CH,CF, group as R, . The efficacy of the different pairs of R, and R, groups in reducing the basicity of the amidine group, as measured by proton affinities, less than (or approximately equal to) that of MA (as a model of the amino alkyl group of NAPF) are discussed below. The reason for lowering the basicity of the tautomeric amidine group is that it must exist at a significant level in the neutral state if it is to be involved in the proton-relay process. The results of the geometry optimizations of methylamine and the MFA structures are reported in Table 1, which provides for each MFA structure: (1) the total and relative molecular energies; (2) the energy difference between the Nl-H and N3-H tautomeric forms; (3) the proton affinity (i.e. the energy difference between the protonated and neutral forms); and (4) the differences of the proton affinity from that of the first MFA structure (250.417 (HF) or 245.146 (MP2) kcalmol-‘) and that of MA (228.374 (HF) or 227.540 (MP2) kcal mol-’ ; see the top of Table 1 or Table 2). When R, = H, one observes that ETN3 = ZTN3, ETCT = ZTCT, ECN3 G ZCN3 and ECCT s ZCCT. Consider the first three MFA analogues in Tables 1 and 2, designated in terms of their (R,,R2) substitution as (H,H), (H,CF,) and (H,C=N). In

M. Sabio and S. Topiol/J. Mol. Struct.

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279 (1993)

the neutral state of their ET structures, the Nl-H tautomer is more stable than the N3-H form, at the HF level, by 0.636 (H,H), 0.409 (H,CF,) and 0.357 (H,C=N) kcalmol-‘, which is clearly consistent with the requirement of the H, -receptor model that the neutral analogue must exist to a significant degree as the Nl-H tautomer. At the MP2 level, in the neutral ET structures, the Nl-H tautomer is less stable than the N3-H form by 0.396 (H,H), 0.413 (H,CF,) and 0.592 (H,C=N) kcalmol-‘; however, this is also consistent with the same requirement, as demonstrated in the following calculations. In the case of (H,H), the ratio of Nl-H to N3-H tautomers is 0.515 (i.e. emAEIRT,where BE = R= E(Nl-H) - E(N3-H) = 0.396 kcalmol-‘, 0.0019872 kcalmol-’ K-‘, and T is taken to be 300K), which means an Nl-H tautomer population of 34.0% (i.e. 100% x 0.515/1.515); the corresponding Nl-H tautomer populations (at 300 K) for (H,CF,) and (H,C=N) are 33.3% and 27.0% respectively. However, at both the HF and MP2 levels, each analogue has a proton affinity that is greater than that of methylamine (see entries in the last column). Therefore the preferred protonation site is expected to be the amidine group, as opposed to an amine group, contrary to the requirement of the model that the tautomeric amidine group must exist at a significant level in the neutral state if it is to be involved in the proton-relay process. With one exception, only a small or negligible population of neutral amidine is expected to exist (the exception occurs for (H,C=N), whose proton affinity relative to that of MA is only 0.404 kcal mol-’ at the MP2 level). Thus, in the design of Hz-receptor agonists, with respect to the examples considered here, R, should not be a hydrogen atom. The correlation of the relative proton affinities with the electron-withdrawing abilities of the R, group (C=N > CF, > H) and the effect of the -CH,CF, group as R, for R, = H compounds are discussed below. When R’ is C-N and R, is H, CF, or C=N, the Nl-H tautomer is more stable than the N3-H form in the neutral structure and all the proton affinities are lower than that of MA; these relationships are

IS-27

19

true at both the HF and MP2 levels. Therefore, based on this model, amidines in which R’ is a cyano group may serve as a starting point for the development of Hz-receptor agonists. The proton affinities relative (last column of Table 1) to that of MA correlate with the generally accepted electronwithdrawing strengths of the R, groups (i.e. CzN > CF, > H); for example, for the ET structures, the magnitudes of the relative proton affinities (kcalmol-‘) are 25.641 (C=N) > 20.011 (CF,) > 9.939 (H) at the HF level; 27.472 (C=N) > 22.482 (CF,) > 13.419 (H) at the MP2 level. The effect of the -CH,CF, group is discussed below. We can examine the effects of each R’ and R, substitutent in lowering the proton affinity of the amidine group. For example, for the ET structures, the replacement of a hydrogen atom at the R2 position by a trifluoromethyl group (i.e. (H,H) to (H,CF,)) lowers the proton affinity of the amidine group by 12.990 kcalmol-’ (HF) or 11.535 kcalmoll’ (MP2) (see Table 1 or Table 2, second column from the right); similarly, (H,H) to (H,C=N) and (H,H) to (CzN,H) result in reductions of 19.213 and 3 1.982 kcal mol-’ (HF) respectively, or 17.203 and 3 1.025 kcal mol-’ (MP2) respectively. Thus the C=N group has a greater effect at the R, position (as demonstrated above) and is presumably more strongly electron-withdrawing than the CF, group. If the effects of the R, and R, groups are additive, then the transformations of (H,H) to (C=N,CF,) and (H,H) to (C=N,C=N) should result in lowering the amidine’s proton affinity by 12.990 + 31.982 = 44.972kcalmoll’ (HF) and 19.213 + 3 1.982 = 51.195 kcal mol-’ (HF) respectively, or 11.535 + 31.025 = 42.560kcalmoll’ (MP2) and 17.203 + 31.025 = 48.228 kcalmol-’ (MP2) respectively. These predictions are close to the actual values of 42.054 and 47.684 kcalmol-’ (HF) respectively, or 40.088 and 45.078 kcalmol-’ (MP2) respectively. The last two compounds in Tables 1 and 2 ((H,CH,CF,) and (C=N,CH,CF,)) have proton affinities and (apparent) relative electron-withdrawing abilities that are, as expected, between

M. Sabio and S. Topiol/J. Mol. Struct. (Theochem)

20

279 (1993)

15-27

TABLE 1 The HF/4-31G*(5D) total and relative molecular energies and proton affinities of N-methylformamidine analogues in various conformations, tautomeric forms” and protonation states=, whose geometries are optimizedb with the 4-31G*(5D) basis set at the Hartree-Fock level Methylformamidine substitution R,,R,

Isomerism’ and protonation state

Methylamine

Neutral Protonated

H, H

ETN3 ETNl ETCT ECN3 ECNl ECCT ZTN3 ZTNl ZTCT ZCN3 ZCNl ZCCT

H, CF,

C=N, H

Relative (kcal mol-i)

- 95.110829 228.374 - 95.474766 0.0

-

228.374

APAw,~ (kcalmol-‘)

_

APA,,r (kcalmol-‘)

0.0

187.906292 187.907305 188.306370 187.910325 187.906146 188.305521 187.906292 187.910055 188.306370 187.910325 187.908356 188.305521

251.053 250.417 0.0 247.989 250.611 0.0 251.053 248.691 0.0 247.989 249.225 0.0

- 0.636

250.417

0.0

22.043

2.622

247.989

- 2.428

19.615

- 2.362

248.691

- 1.726

20.317

1.236

247.989

- 2.428

19.615

523.205202 523.205854 523.584218 523.201882 523.200085 523.579674 523.205202 523.209118 523.584218 523.201882 523.203738 523.579674

237.836 237.427 0.0 237.068 238.195 0.0 237.836 235.379 0.0 237.068 235.903 0.0

- 0.409

237.427

- 12.990

9.053

1.128

237.068

- 13.349

8.694

- 2.457

235.379

- 15.038

7.005

- 1.165

235.903

- 14.514

7.529

ZCCT = ECCT

-

ETN3 ETNl ETCT ECN3 ECNl ECCT ZTN3 ZTNl ZTCT ZCN3 ZCNl ZCCT

-279.538955 - 279.539524 - 279.907971 - 279.541435 - 279.536373 - 279.906062 -279.538955 - 279.542780 - 279.907971 -279.541435 - 279.539624 - 279.906062

231.561 231.204 0.0 228.807 23 1.982 0.0 231.561 229.161 0.0 228.807 229.943 0.0

- 0.357

231.204

- 19.213

2.830

3.176

228.807

- 21.610

0.433

- 2.400

229.161

-21.256

0.787

1.137

228.807

-21.610

0.433

-

229.967 218.435 0.0 228.732 218.673

- 11.532

218.435

- 31.982

- 9.939

- 10.060

218.673

-31.744

- 9.701

E ZTCT = ZCN3 = ZCCT = ETN3 3 ETCT = ECN3 = ECCT E ZTN3 = ZTCT = ZCN3 = ZCCT = ETN3 = ETCT E ECN3

ZCNl

H, C=N

Total (a.u.)

E(NI) - E(N3)d Proton (kcal mol-‘) affinity (kcal mol-‘)

-

ETN3 ETNl ETCT ECN3 ECNl ECCT ZTN3 ZTNl ZTCT ZCN3

= ZTN3

Energy

ETN3 ETNl ETCT ECN3 ECNl

= ZTN3 = ZTCT = ZCN3 = ZCCT 3 ETN3 = ETCT = ECN3 = ECCT

279.526990 279.545367 279.893465 279.534612 279.550643

M. Sabio and S. Topiol/J. Mol. Struct. TABLE

Isomerism’ and

substitution

protonation

R,,R,

state

21

15-27

CF,

Relative

(a.u.)

(kcal mol-‘)

- 279.899120

0.0

- 279.532269

227.410

ZTNl

- 279.552298 - 279.894766

214.902 0.0

ZCN3

-279.538782

223.216

ZCNl

- 279.550529

215.844

ZCCT

- 279.894499

0.0

ETN3

-614.822690

217.426

ETNl

-614.837132

208.363

ETCT

-615.169180 -614.823111

0.0 218.667

ECCT

- 614.837883 -615.171579

209.397 0.0

ZTN3

-614.820822

217.486

ZTNl

- 614.839294

205.895

ZTCT

-615.167408

ZCN3

- 614.818598

212.233

ZCNl

- 614.829706

205.263

ZCCT

-615.156813

0.0

ECNl

H, CH,CF,

Total

ECCT

ECN3

C=N

Energy

ZTN3 ZTCT

C=N,

279 (1993)

1 (continued)

Methylformamidine

C=N,

(Theochem)

ETN3

-371.154053

211.694

-371.168334

202.733

ETCT ECN3

- 371.491409 -371.160422

0.0 211.363

ECNl

-371.172139

204.011

ECCT ZTN3

- 371.497252 -371.154279

0.0 211.296

ZTNl

-371.172281

200.000

ZTCT ZCN3

- 371.491001 - 371.160336

0.0 206.692

ZCNl ZCCT

-371.168742 - 371.489722

201.418 0.0

ETN3 = ZTN3

- 562.212337

246.280

- 562.207690 - 562.211080

249.195 247.068

ETNl

- 562.213045

245.835

ETCT = ZTCT

- 562.208235 - 562.604639

248.854 0.106

ECN3 = ZCN3

- 562.604808 - 562.205936

0.0 247.623

- 562.208443

246.050

- 562.205851 - 562.204259

247.611 248.676

- 562.204835

248.314

- 562.600549 - 562.212337

0.0 246.280

- 562.207690

249.195

- 562.211080

247.068

ECCT = ZCCT ZTN3 = ETN3

Proton

(kcal mol-I)

affinity

APA,we (kcal mol-‘)

APAMAf (kcal mol-‘)

(kcal mol-‘)

- 12.569

214.902

- 35.515

- 13.472

- 7.311

215.844

- 34.573

- 12.530

- 9.063

208.363

- 42.054

- 20.011

- 9.270

209.397

-41.020

- 18.977

- 11.591

205.895

- 44.522

- 22.419

- 6.970

205.263

-45.154

-23.111

- 8.962

202.133

- 47.684

- 25.641

- 7.352

204.011

- 46.406

- 24.363

- 11.296

200.000

- 50.417

-28.374

- 5.275

201.418

- 48.999

- 26.956

- 0.444

245.835

- 4.582

17.461

1.626

246.050

- 4.361

17.676

246.132

- 4.285

17.758

0.0

ETNl

ECNl

E(N1) - E(N3)d

-0.148

22

M. Sabio and S. Topiol/J. Mol. Struct.

(Theochem)

279 (1993)

15-27

TABLE 1 (continued) Methylformamidine substitution R,,R,

Isomerism” and protonation state

Energy Total (a.u.)

Relative (kcal mol-‘)

ZTNl ZTCT = ETCT

-

562.212571 562.604639 562.604808 562.205936 562.208443 562.206198 562.206639 562.206407 562.600549

246.132 0.106 0.0 247,623 246.050 247.459 247.182 247.327 0.0

- 653.829764 - 653.830287 - 653.825914 -653.847319 - 653.842354 - 654.190600 -654.191317 -653.831131 .--653.848363 -653.846537 - 654.195561 - 653.831612 - 653.831075 - 653.852763 - 654.193867 - 653.833207 - 653.845684 - 654.188946

226.878 226.550 229.294 215.862 218.978 0.450 0.0 228.683 217.870 219.016 0.0 227.318 227.655 214.045 0.0 223.229 215.400 0.0

ZCN3 = ECN3 ZCNl

ZCCT = ECCT C=N, CH,CF,

ETN3

ETNl ETCT ECN3 ECNl ECCT ZTN3 ZTNl ZTCT ZCN3 ZCNl ZCCT

E(N1) - E(N3)d Proton (kcal mol-‘) affinity (kcal mol-I)

APA,,” (kcal mall’)

APAnAf (kcal mol-‘)

1.132

246.050

- 4.367

17.676

- 10.687

215.862

- 34.555

- 12.512

110.813

217.870

- 32.547

- 10.504

- 13.273

214.045

- 36.372

- 14.329

- 7.829

215.400

- 35.017

- 12.974

a See Fig. 1. bNo geometric constraints were imposed. “The designation of the more stable neutral tautomer is in bold type. dA negative value of the energy difference (in this column) between the Nl-H and N3-H tautomers indicates that the Nl-H tautomer is more stable. eProton affinity relative to MFA (250.417 kcalmol-I); a negative value indicates that the proton affinity is lower than that of MFA. fProton affinity relative to MA (228.374 kcalmol-‘); a negative value indicates that the proton affinity is lower than that of MA.

those of (R, ,H) and (R, ,CF3). The trifluoromethyl portion of CH,CF, lowers the basicity of the amidine group by (presumably) withdrawing electronic charge through the adjacent methylene group. Thus the results of this study are consistent with the relative electron-withdrawing capabilities: CkN > CF, > CH,CF, > H. For every ET compound, there is a strong correlation between the proton affinity and the

energy difference between the Nl-H and N3-H tautomeric forms. In Fig. 2, the proton affinities relative to that of methylamine are plotted as a function of the energy of tautomerization; negative values along the abscissa and ordinate axes represent more stable Nl-H (versus N3-H) tautomers and lower proton affinities than that of MA respectively. In quadrant B of Fig. 2, the relationship

23

M. Sabio and S. TopiollJ. Mol. Struct. (Theochem) 279 (1993) 15-27 TABLE 2

The MP2/4-31G*(5D) total and relative molecular energies and proton affinities of N-methylformamidine analogues in various conformations, tautomeric forms” and protonation statesa, whose geometries are optimizedb with the 4-31G*(5D) basis set at the Hartree-Fock

level

Methylformamidine

Isomerism’ and

substitution

protonation

R,,R,

state

Methylamine

(kcal mol-‘)

APA,rAe (kcal mol-‘)

APA,,r (kcal mol-‘)

227.540

-

ETN3 = ZTN3

- 188.480993

245.146

0.396

245.146

0.0

17.607

ETNl ETCT = ZTCT

- 188.480362

245.542

- 188.871658 - 188.484393 - 188.478676

0.0 242.056 245.644

3.588

242.056

- 3.090

14.516

- 188.870134

0.0

- 188.480993

245.146

Z-ml

- 188.483182

243.773

ZTCT - ETCT ZCN3 = ECN3

- 188.871658 - 188.484393

0.0 242.056

ZCNl

- 188.480983

244.196

- 188.870134

0.0

ETN3 = ZTN3 ETNl

- 524.408228 - 524.407570

233.611 234.024

ETCT = ZTCT

- 524.780511

0.0

ECN3 E ZCN3 ECNl

- 524.406362

232.194

- 524.402552 - 524.776386

234.585 0.0

- 524.408228

ZCN3 = ECN3

-524.411308 - 524.780511 - 524.406362

ZCNl

- 524.406825

23 1.903

- 524.776386

0.0

ETN3 = ZTN3 ETNl

- 280.384979 - 280.384035

227.944 228.536

ETCT 3 ZTCT ECN3 = ZCN3

- 280.748230 - 280.388010 -280.381410

0.0 224.837 228.979

-280.746312 - 280.384979

ZCCT

= ETN3

= ECCT

ECCT = ZCCT ZTN3 = ETN3

ZTNl ZTCT

ZCCT

= ETCT

= ECCT

ECNl ECCT = ZCCT ZTN3 = ETN3

ZTNl ZTCT

= ETCT

ZCN3 = ECN3 ZCNl

- 1.374

16.233

2.140

242.056

- 3.090

14.516

0.413

233.611

- 11.535

6.071

2.391

232.194

- 12.953

4.654

233.611

- 1.932

231.679

- 13.468

4.139

231.679 0.0 232.194

- 0.291

23 1.903

- 13.244

4.363

0.592

227.944

- 17.203

0.404

4.142

224.837

- 20.309

- 2.702

0.0 227.944

- 1.859

226.085

- 19.061

- 1.455

- 280.387941 - 280.748230 - 280.388010

226.085 0.0 224.837

1.713

224.837

- 20.309

- 2.702

- 280.385281

226.550

- 11.284

214.121

- 31.025

- 13.419

- 10.287

214.265

- 30.881

- 13.275

0.0

ETN3

225.405

ETNl

-280.387930

214.121

ETCT ECN3

-280.729153 -280.375900 -280.392294

0.0 224.552 214.265

ECNl

.\ 243.773

- 280.369948

= ECCT

0.0

- 1.374

- 280.746312

ZCCT C=N, H

(an.)

affinity (kcalmol-‘)

-

ZTN3

H, C=N

Relative

Proton

(kcal mol-‘)

227.540 0.0

ECN3 = ZCN3 ECNl ECCT = ZCCT

H, CF,

Total

E(N1) - E(N3)d

- 95.404849 - 95.767457

Neutral Protonated

H,H

Energy

24 TABLE

hf. Sabio and S. TopioljJ. Mol. Struct. (Theochem) 279 (1993) 15-27 2 (continued)

Methylformamidine

Isomerism’ and protonation

Energy

substitution R,,R,

state

Total (a.u.)

CzN, CF,

CEN, C=N

H, CH,CF,

0.0

- 280.374063

222.756

ZTNl

-280.393245

210.719

ZTCT

- 280.729048

0.0

ZCN3 ZCNl

- 280.379462

218.675

ZCCT

- 280.390908 - 280.727943

211.492 0.0

ETN3 ETNl

-616.294445 -616.310531

215.152 205.058

ETCT ECN3

-616.637312 -616.295559

0.0 215.976

ECNl ECCT

-616.311365

206.058

ZTN3

-616.293162

214.870

ZTNl

-616.313363

202.194

ZTCT

- 616.635580

ZCN3

-616.291861

209.460

ZCNl

.-616.304680

201.416

ZCCT

- 616.625657

APA,,” (kcalmol-I)

APAMAf (kcalmol-‘)

- 12.037

210.719

- 34.427

- 16.820

-7.183

211.492

- 33.654

- 16.047

- 10.094

205.058

- 40.088

- 22.482

-9.918

206.058

- 39.089

-21.482

- 12.677

202.194

- 42.953

- 25.346

18.044

201.416

- 43.730

-26.123

- 10.057

200.068

- 45.078

- 27.472

- 8.503

201.198

- 43.948

- 26.341

- 12.067

197.239

- 47.908

- 30.301

-6.169

198.414

- 46.732

-29.126

0.580

240.626

- 4.520

13.086

2.822

240.133

- 5.013

12.594

0.870

240.626

- 4.520

13.086

0.0

0.0

0.0

ETN3

-372.269066

210.125

ETNl ETCT

- 372.285093

200.068

- 372.603922

0.0

ECN3

- 372.275095

209.702

ECNl

- 372.288646

201.198

ECCT ZTN3

- 372.609276 - 372.269875 - 372.289105

0.0 209.306 197.239

ZTCT ZCN3

- 372.603425

0.0

- 372.275982

204.583

ZCNl

-372.285812

198.414

ZCCT

- 372.602005

0.0

ETN3 3 ZTN3

- 563.546597

240.626

- 563.540154 - 563.544991

244.669 241.633

ETNl

- 563.545673 - 563.538831

241.206 245.499

ETCT = ZTCT

- 563.930037

0.014

ECN3 = ZCN3

- 563.930059 - 563.540244 - 563.543167

0.0 241.968 240.133

ECNl

- 563.538670

242.956

- 563.535359 - 563.537730

245.033 243.545

- 563.925844 - 563.546597

0.0 240.626

- 563.540154 -563.544991

244.669 241.633

ECCT E ZCCT ZTN3 = ETN3

affinity (kcal mol-I)

(kcal mol-‘)

- 280.733747

ZTNl

Proton

Relative

ECCT ZTN3

- 616.639739

E(N1) - E(N3)d (kcalmol-‘)

25

A4. Sabio and S. Topiol/J. Mol. Struct. (Theochem) 279 (1993) 15-27 TABLE 2 (continued) Methylformamidine substitution R,,R,

Isomerism’ and protonation state

ZTNI ZTCT = ETCT ZCN3 = ECN3 ZCNI

ZCCT = ECCT C=N, CH,CF,

ETN3

ETNl ETCT ECN3 ECNl ECCT ZTN3 ZTNl ZTCT ZCN3 ZCNl ZCCT

Energy Total (au.)

Relative (kcal mol-I)

- 563.544991 - 563.545211 - 563.930037 - 563.930059 - 563.540244 -563.543167 - 563.539184 - 563.539852 - 563.538811 - 563.925844

241.633 241.496 0.014 0.0 241.968 240.133 242.633 242.214 242.867 0.0

- 655.433373 - 655.433862 - 655.427679 - 655.450664 - 655.443845 - 655.787813 - 655.788651 - 655.433659 -655.451475 - 655.447885 -655.792181 - 655.434724 - 655.432686 - 655.455892 - 655.790603 - 655.436580 - 655.449584 - 655.785969

222.941 222.633 226.513 212.090 216.369 0.526 0.0 224.976 213.796 216.049 0.0 223.317 224.596 210.034 0.0 219.245 211.085 0.0

E(N1) - E(N3)d Proton (kcalmol-‘) affinity (kcal mol-I)

2.080

APA,,” (kcalmol-I)

APA,,’ (kcalmol-‘)

240.133

- 5.013

12.594

212.090

- 33.056

- 15.449

- 11.180

213.796

- 31.350

- 13.743

- 13.283

210.034

-35.112

- 17.505

211.085

- 34.062

- 16.455

“See Fig. 1. bNo geometric constraints were imposed in the HF/4-31G*(5D) geometry optimizations. When there are two or more conformers of a particular isomeric form (e.g. ETN3), their order is the same as their order in Table 1. “The designation of the more stable neutral tautomer is in bold type. dA negative value of the energy difference (in this column) between the Nl-H and N3-H tautomers indicates that the Nl-H tautomer is more stable. ‘Proton affinity relative to MFA (245.146 kcal mol-I); a negative value indicates that the proton affinity is lower than that of MFA. ‘Proton affinity relative to MA (227.540 kcal mol-I); a negative value indicates that the proton affinity is lower than that of MA.

APAM* (kcalmol-‘) = - 62.339[E(Nl-H) - E(N3-H)] - 15.923 where APA,, = PA - PA,,, describes the behavior (with r2 = 0.783) of the RI = H compounds studied herein at the HF level. (The 3 value of the corresponding MP2 line is only 0.211 and therefore its equation is not reported.) One observes that if the HF line segment is continued

toward negative APAhlA (i.e. if this relationship is found for other R, functional groups beyond one of the extreme points of this set of four), there may be points on this line that could simultaneously have a (comparable or) lower proton affinity than that of MA and have in the neutral structure an Nl-H tautomer that is more stable (or is less stable by no greater than approximately 1 kcalmol-‘) than the

26

M. Sabio and S. Topiol/J. Mol. Struct. (Theochem) 279 (1993) 15-27 30

tion of the amidine group occurs to a greater degree than protonation at the amine group. In any event, a similar analysis must be performed on an analogous set of compounds that possess a protonation site (e.g. a positive point charge, a protonated amine group, etc.) to determine which (R,,R,) pair provides the compound, in both the netural and protonated states, with the characteristics consistent with the proposed model.

i MP2

HF

*PAMA

W,H)’

20-

(H,CH,CFJ

n ix (H,H)

; x (H,CH,CFJ

(kcallmol~ 1 o-

(H,CF,)

‘p I

Conclusions

-15

-10

0

-5

E(N1)- E(Ns)

5

(kcalimol)

Fig. 2. The HF and MP2 relationships of the proton affinities relative to that of methylamine (APA& and the energy of tautomerization for the analogues of this study.

N3-H form. In quadrant C, the relationship APA,,

(kcalmol-‘)

= - 5.399[E(Nl-H)

- E(N3-H)] - 71.347 describes the behavior (with r* = 0.903) of the R, = C-N compounds studied herein at the HF level. The MP2 results are described by the relationship APA,,

(kcalmol-‘)

- E(N3-H)]

= - 9.903[E(Nl-H)

- 123.637

with r* = 0.763. All compounds represented by points in (or very close to) quadrant C can achieve the two conditions necessary for the recognition (after the addition of an amino alkyl group) and activation at the H, receptor, i.e. in the neutral state a significant population of the Nl-H tautomer must exist and the amidine group must exist at a significant level in the neutral state. Compounds represented by points that are only slightly outside quadrant C may also be considered with one or two compromises: a significant population of the N3-H tautomer exists in the neutral state and/or protona-

The computational investigation of a previously proposed model of recognition and activation at the H, receptor has provided important insights into the design of H,-receptor agonists containing an amidine group rather than an imidazole ring as in histamine. In this study, we examined analogues of N-methylformamidine, in various isomeric and tautomeric forms, as models of N-(3-aminopropyl)formamidine (NAPF) in our previous study. We previously concluded that NAPF could not serve as an H,-receptor agonist because, contrary to the proposed H,-receptor model, the amidine, not the amine group, would be preferentially protonated. The derivatives of N-methyformamidine in the present work are substituted at an amidine carbon or nitrogen position (preserving the possibility of tautomerism) with functional groups of varying electron-withdrawing strengths. The calculations reveal that some of the analogues possess a proton affinity lower than (or comparable to) that of a model of the NAPF’s amino alkyl side-chain (methylamine) and, at the same time, exist to a significant degree (at the levels of theory employed in this study) as the Nl-H tautomer in the neutral state; both of these attributes are required by the proposed model. Thus it seems possible to design amidines as H,-receptor agonists. We showed that the proton affinities are correlated with the electronic effects of the substituents and with the energy difference between the Nl-H and N3-H tautomers. Additional calculations on amineprotonated analogues of the compounds studied

M. Sabio and S. Topiol/J. Mol. Struct.

(Theochem)

279 (1993)

herein are necessary to determine whether the protonated form exists to a significant degree as the N3-H tautomer (a requirement of the model).

27

15-27

3 4 5

Supplementary material available 6

A table of all the structural parameters obtained at the HF/4-3 1G*(5D) level for MFA is available from the authors. Acknowledgments

We are grateful to P.W. Erhardt, J. Lampe and WC. Lumma, Jr., for valuable discussions. References 1 M. Sabio and S. Topiol, Eur. J. Med. Chem., 24 (1989) 189-192. 2 H. Weinstein, E. Chou, C.L. Johnson, S. Kang and J.P. Green, Mol. Pharmacol., 12 (1976) 738-745.

7 8 9 10 11 12 13

G.J. Durant, C.R. Ganellin and M.E. Parsons, J. Med. Chem., 18 (1975) 905-909. S. Topiol, H. Weinstein and R. Osman, J. Med. Chem., 27 (1984) 1531-1533. G. Hafelinger, in S. Patai (Ed.), The Chemistry of Amidines and Imidates, London, 1975, p. 1. A.H. Owens, R.R. Goehring, J.W. Lampe, P.W. Erhardt, W.C. Lumma, Jr., and J. Wiggins, Eur. J. Med. Chem., 23 (1988) 295-300. P.W. Erhardt, J. Med. Chem., 30 (1987) 231-237. B. Permanetter, G. Baumann, J. Dorner, W. Schunack and H. Blomer, Agents Actions, 16 (1985) 215-218. G. Baumann, B. Permanetter and A. Wirtzfeld, Pharmacol. Ther., 24 (1984) 165-177. C.C.J. Roothaan, Rev. Mod. Phys., 32 (1960) 179. R. Ditchfield, W.J. Hehre and J.A. Pople, J. Chem. Phys., 54 (1971) 724. C. Msller and M.S. Plesset, Phys. Rev., 46 (1934) 618. M.J. Frisch, M. Head-Gordon, G.W. Trucks, J.B. Foresman, H.B. Schlegel, K. Raghavachari, M. Robb, J.S. Binkley, C. Gonzalez, D.J. DeFrees, D.J. Fox, R.A. Whiteside, R. Seeger, CF. Melius, J. Baker, R.L. Martin, L.R. Kahn, J.J.P. Stewart, S. Topiol and J.A. Pople, GAUSSIAN 90, Revision J, Gaussian Inc., Pittsburgh, PA, 1990.