- Email: [email protected]
A correlation between geometric features and analgesic activity for a series of cannabinoid compounds
Journal of
MOLECULAR STRUCTURE ELSEVIER
Journal of Molecular Structure 441 (1998) 97-100 Short communication
A correlation between geometric features and analgesic activity for a series of cannabinoid compounds S a u l o L. d a S i l v a , A g n a l d o A r r o i o , A l b r r i c o B.F. d a S i l v a * ,
Milan Trsic
Departamento de Quimica e Fisica Molecular, Instituto de Quimica de Sro Carlos, Universidade de S~o Paulo, C.P. 780. 13560-970. SP S~o Carlos, Brazil
Received 4 April 1997; accepted 13 June 1997
Keywords: Analgesic activity; Cannabinoids; Geometric features
Cannabinoids are the natural compounds of the plant Cannabis sativa and have been the subject of chemical, pharmacological and clinical investigations in recent decades. Preparations of the plant have been used by man for over 5000 years [ 1] and C. sativa is known to contain more than 400 chemical compounds including more than 60 compounds of the cannabinoid type [2]. Research suggests the potential of several cannabinoids as therapeutical agents [3] and these findings have been partially responsible for an increasing interest in the chemistry and pharmacology of the cannabinoids. Nevertheless, despite many pharmacological and biochemical investigations, little is still known about the molecular basis of action of the cannabinoid compounds. Cannabinoids are thought by some to interact with a specific receptor in the central nervous system [4] and others hold that cannabinoids exert their effect by interactions with membranes [5-7]. Recently, we studied a series of cannabinoids with * Corresponding author, e-mail: [email protected]
a semiempirical quantum chemical approach focusing psychoactivity [8]. In this work, we explored a therapeutical aspect of cannabinoid compounds, i.e. the analgesic potency. Here, we study the correlations between geometric structure and analgesic activity for a series of cannabinoids with different analgesic potency and we show that conformational changes seem to correlate with analgesic activity. The characterization of the geometric structure of the cannabinoid compounds studied here is made by using the interactive molecular modeling program PC MODEL [9] which uses the features of Allinger's MMX force field including pivalence electron self-consistent field (Pi-VESCF) calculations [9]. The MMX force field is an extension of the MM2 force field of Allinger [10,1 i] with the Pi-VESCF routines taken from the MMP1 program developed by Allinger and Sprague [12,13]. The potential energy parameters as well as the standard geometry optimization routines built-in the PC MODEL were used in all molecular geometry calculations. Although having different chemical structures, the analgesics in this study present some common
0022-2860/98/$19.00 © 1998 Elsevier Science B.V. All rights reserved PII S0022-2860(97)00274-3
98
S.L. da Silva et al./Journal of Molecular Structure 441 (1998) 97-100
R1
R1 , f~0
112
7
6
B
4
2. 113
Fig. 1. Typical cannabinoid structure.
features [14] (for the c a n n a b i n o i d compounds, see Fig. 1): 1. a quaternary carbon atom (C1 1); 2. an aromatic moiety attached to the quaternary carbon atom (C6 and C1 1); 3. a hydroxyl or oxo group in meta position relative to the quaternary carbon atom. Fig. 1 shows the typical chemical structure of a c a n n a b i n o i d compound. In particular, the analgesia presented by the cannabinoids, in terms of functional groups are based on three principal aspects [ 1 5 - 1 8 ] (see Fig. 1): 1. a hydroxyl group (R1) in the A ring in the equatorial position; 2. a hydroxyl group (R2) in the C ring forming a plane with C6 and C5 or C4 and C5; 3. one hydrophobic side chain (R3) in the C ring in meta position relative to the hydroxyl group (R2). For the correlation study between geometric structure and analgesic activity, we have selected 14 classical and nonclassical c a n n a b i n o i d s quoted in the literature as having analgesic properties [15]. The selection of the 14 c a n n a b i n o i d s was made by taking into account the analgesic potency compared with morphine. In Figs. 2 - 4 , we show the chemical structure of these compounds.
nO" Fig. 2. CP-55244 (Ref. [15]), compound 1.
Fig. 3. CP-55940 (Ref. [15]), compound 2, R1 = OH R2 = (CH2)30H; derivative of BRL-6155 (Ref. [15]), compound 3, R1 = OH (equatorial) R2 = H; derivative of BRL-6155 (Ref. [15]), compound 4, RI = O R2 = H; derivative of BRL-6155 (Ref. [15]), compound 5, RI = OH (axial) R2 = H. The chosen c a n n a b i n o i d s were grouped into three categories, i.e.: 1. Group I: c o m p o u n d s from 1 to 5. Such c o m p o u n d s have an analgesic potency superior or equivalent to morphine; 2. Group H: c o m p o u n d s from 6 to 9. These compounds present an analgesic potency inferior to morphine; 3. Group III: c o m p o u n d s from 10 to 14. These compounds are inactive or present a very low analgesic potency.
D u r i n g the optimization process using the program PC M O D E L , special attention was given to some geometric parameters in the functional groups that confer
R1
Fig. 4. Derivative of 9-nor-9-/3-hydroxy-HHC,compound 6, R1 = OH (equatorial) R2 = OH R3 = OCH(CH3)(CH2)CrH6; Canbisol, compound 7, R1 = OH (equatorial) R2 = OH R3 = C(CH3)2(CH2)sCH3; derivative of 9-nor-9-/3-hydroxy-HHC, compound 8, R1 = OH (equatorial) R2 = OH R3 = CH(CH3)CH(CH3(CH2)4CH3; 9-nor9-/3-hydroxy-HHC,compound 9, RI = OH (equatorial) R2 = OH R3 = (CH2)4CH3; 9-a-hydroxy-&7-THC, compound 10 RI = OH (axial) R2 = OH R3 = (CH2)4CH3; 1l-hydroxy-A 9-THC, compound 11, RI = OH R2 = OH R = ( C H 2 ) a C H 3 ; derivative of 9-nor-9-/3hydroxy-HHC, compound 12, R 1 = OH (equatorial) R2 = COOH R3 = OCH(CH3)(CH2)3CrH6; derivative of 9-nor-9-B-hydroxy-HHC, compound 13, R1 = OH (equatorial) R2 = CH2OH R3 = OCH(CH3)(CH2)3CrH6; 9-nor-943-hydroxy-HHC, compound 14, RI = OH (axial) R2 = OH R3 = (CHz)aCH3.
S.L. da Silva et al./Journal of Molecular Structure 441 (1998) 97-100
99
Table 1 Optimized geometric parameters and analgisic activity for the cannabinoid compounds studied Compound number (See Figs. 2-4)
Distance between the oxygens (,~)
Torsion angle between rings A and C (degrees)
1 2 3 4 5 6 7 8 9 10 11 12 13 14
6.46 6.45 6.13 5.64 4.88 5.08 5.13 5.01 5.12 5.22 5.00 5.53 5.12 4.38
-150.77 -143.53 -116.41 -116.36 -136.54 -65.94 -68.98 -67.36 -67.10 -72.64 -67.12 -65.42 -68.99 -65.58
analgesia to the cannabinoid compounds, namely (see Fig. 1 for all cases): 1. the distance between the oxygen atom in the hydroxyl group of the A ring and in the phenylic ring (R1 and R2, respectively); 2. the torsion angle between the A and C rings defined by C5, C6, C l l and C10; 3. the torsion angle between the side chain R3 and the C ring, defined by C2, C3, C I ' , C2'. Table 1 gives the geometrical parameters found in our geometry optimization calucations for all compounds studied and in the last column we have outlined if the analgesic potency of the compound is superior or equivalent or inferior when compared with the analgesic potency of morphine, or even if the cannabinoid compound is inactive. From Table 1 we can see that the distance oxygen atoms of the hydroxyl group in the A ring and in the phenylic ring show some tendency for increased activity correlating with larger O - O distances. On the other hand, the torsion angles between the A and C rings defined by C5, C6, C11 and C10 present a more clear-cut correlation with the analgesic potency. Indeed, in Table 1, one can notice that if the torsion angle between the A and C rings is higher than 100 °, the analgesic potency of the cannabinoid will be
Torsion angle between ring C and the R3 chain (degrees) 133.38 132.10 125.32 122.60 136.65 123.20 110.96 112.93 110.28 88.61 89.01 92.49 92.43 79.00
Reported potencies (Ref. [13])
60-190 x morphine 8-25 × morphine 2 - 5 × morphine Similar to morphine Similar to morphine Potent Potent Potent Potent Some potency Some potency Low Potency Low potency Inactive
stronger or similar to the morphine. If this torsion angle is lower than 100 °, the cannabinoid can still present analgesic potency, but it will be lower than morphine, or even it will be inactive. In addition, for the torsion angles between the side chain R3 and the C ring in the cannabinoids studied, we can see that if the torsion angle is higher than 100 °, the compound will present at least an analgesic potency close to morphine. If the torsion angle is inferior to 100 °, the compound will present a very low analgesic potency, or even it will be inactive. ' It seems to be the combination of these two outcomes, the torsion angles between the A and C rings and between the side chain R3 and C ring give us some insight on the analgesic potency of the cannabinoid compounds studied here. If the torsion angles between the A and C rings and the side chain R3 and the C ring are both higher than 100 °, the compound will have a very strong analgesic activity (at least close to that presented by morphine). If the torsion angle between the A and C rings is lower than 100 °, but the torsion angle between the R3 and C rings is higher than 100 °, the compound will still present analgesic activity, but it will be inferior to the analgesic potency of morphine. If both torsion angles between the A and C rings and between the R3
100
S.L. da Silva et al./Journal of Molecular Structure 441 (1998) 97-100
and C rings are lower than 100 °, the c o m p o u n d will have a low analgesic activity, or it will e v e n be inactive. As a final remark, we ought to stress the qualitative character of our conclusions. It is clear that the potencies listed in the last c o l u m n o f Table 1 are qualitative. M o r e o v e r , Ref. [15] is a survey of several reports in which analgesic potency was meassured with different methods, Thus, what stands are critical g e o m e t r i c parameter values b e l o w or above which there is modification in analgesic activity.
Acknowledgements W e are grateful for financial support from F A P E S P , C N P q and F I N E P (Brazilian Agencies).
References [1] N.R. Farnsworth, J. Am. Pharm. Assoc. N59 (1969) 410. [2] C.E. Turner, M.A. Elsohly, E.G. Boeren, J. Nat. Products. 43 (1980) 169.
[3] Marihuana Research Findings, NIDA Research Monograph Series 31, U.S. Department of Health and Human Services, Rockville, MA, 1980. [4] J.A. Dill, A.C. Howlett, J. Pharm. Exp. Ther. 244 (1988) 1157. [5] S.H. Roth, P.J. Williams, J. Pharm. Pharmacol. 31 (1979) 224. [6] S. Burstein, S.A. Hunter, Biochem. Pharmacol. 27 (1978) 1275. [7] A. Makriyannis, S. Fesik, R. Kriwacki, in: A. Makriyannis (Ed.), New Methods in Drug Research, Prous, Barcelona, 1985. [8] A.B.F. da Silva, M. Trsic, J. Mol. Struct. 356 (1995) 247. [9] PC MODEL program (version 3.0), Serena Software, Bloomington, University of Indiana, IN 47402-3076, 1989. [10] MM2 (77) program, Quantum Chemistry Program Exchange Indiana, Bloomington, IN 47405, Program 395. [11] N.L. Allinger, J. Am. Chem. Soc. 99 (1977) 8127. [12] MMPI program, Quantum Chemistry Program Exchange Indiana, Bloomington, IN 47405, Program 318. [13] N.L. Allinger, J.T. Sprague, J. Am. Chem. Soc. 95 (1973) 3893. [14] A. Korolkovas, J.H. Burckhalter, Essentials of Medicinal Chemistry, Wiley, New York, 1976. [15] R.K. Razdan, Pharmacol. Rev. 38 (1986) 75. [16] A.C. Howlett, M.R. Johnson, L.S. Melvin, G.M. Milne, Mol. Pharmacol. 33 (1988) 297. [17] P.H. Reggio, K.V. Greer, S.M. Cox, J. Med. Chem. 32 (1989) 1630. [18] S.F. Semus, B.R. Martin, Life Sci. 46 (1990) 1781.
MOLECULAR STRUCTURE ELSEVIER
Journal of Molecular Structure 441 (1998) 97-100 Short communication
A correlation between geometric features and analgesic activity for a series of cannabinoid compounds S a u l o L. d a S i l v a , A g n a l d o A r r o i o , A l b r r i c o B.F. d a S i l v a * ,
Milan Trsic
Departamento de Quimica e Fisica Molecular, Instituto de Quimica de Sro Carlos, Universidade de S~o Paulo, C.P. 780. 13560-970. SP S~o Carlos, Brazil
Received 4 April 1997; accepted 13 June 1997
Keywords: Analgesic activity; Cannabinoids; Geometric features
Cannabinoids are the natural compounds of the plant Cannabis sativa and have been the subject of chemical, pharmacological and clinical investigations in recent decades. Preparations of the plant have been used by man for over 5000 years [ 1] and C. sativa is known to contain more than 400 chemical compounds including more than 60 compounds of the cannabinoid type [2]. Research suggests the potential of several cannabinoids as therapeutical agents [3] and these findings have been partially responsible for an increasing interest in the chemistry and pharmacology of the cannabinoids. Nevertheless, despite many pharmacological and biochemical investigations, little is still known about the molecular basis of action of the cannabinoid compounds. Cannabinoids are thought by some to interact with a specific receptor in the central nervous system [4] and others hold that cannabinoids exert their effect by interactions with membranes [5-7]. Recently, we studied a series of cannabinoids with * Corresponding author, e-mail: [email protected]
a semiempirical quantum chemical approach focusing psychoactivity [8]. In this work, we explored a therapeutical aspect of cannabinoid compounds, i.e. the analgesic potency. Here, we study the correlations between geometric structure and analgesic activity for a series of cannabinoids with different analgesic potency and we show that conformational changes seem to correlate with analgesic activity. The characterization of the geometric structure of the cannabinoid compounds studied here is made by using the interactive molecular modeling program PC MODEL [9] which uses the features of Allinger's MMX force field including pivalence electron self-consistent field (Pi-VESCF) calculations [9]. The MMX force field is an extension of the MM2 force field of Allinger [10,1 i] with the Pi-VESCF routines taken from the MMP1 program developed by Allinger and Sprague [12,13]. The potential energy parameters as well as the standard geometry optimization routines built-in the PC MODEL were used in all molecular geometry calculations. Although having different chemical structures, the analgesics in this study present some common
0022-2860/98/$19.00 © 1998 Elsevier Science B.V. All rights reserved PII S0022-2860(97)00274-3
98
S.L. da Silva et al./Journal of Molecular Structure 441 (1998) 97-100
R1
R1 , f~0
112
7
6
B
4
2. 113
Fig. 1. Typical cannabinoid structure.
features [14] (for the c a n n a b i n o i d compounds, see Fig. 1): 1. a quaternary carbon atom (C1 1); 2. an aromatic moiety attached to the quaternary carbon atom (C6 and C1 1); 3. a hydroxyl or oxo group in meta position relative to the quaternary carbon atom. Fig. 1 shows the typical chemical structure of a c a n n a b i n o i d compound. In particular, the analgesia presented by the cannabinoids, in terms of functional groups are based on three principal aspects [ 1 5 - 1 8 ] (see Fig. 1): 1. a hydroxyl group (R1) in the A ring in the equatorial position; 2. a hydroxyl group (R2) in the C ring forming a plane with C6 and C5 or C4 and C5; 3. one hydrophobic side chain (R3) in the C ring in meta position relative to the hydroxyl group (R2). For the correlation study between geometric structure and analgesic activity, we have selected 14 classical and nonclassical c a n n a b i n o i d s quoted in the literature as having analgesic properties [15]. The selection of the 14 c a n n a b i n o i d s was made by taking into account the analgesic potency compared with morphine. In Figs. 2 - 4 , we show the chemical structure of these compounds.
nO" Fig. 2. CP-55244 (Ref. [15]), compound 1.
Fig. 3. CP-55940 (Ref. [15]), compound 2, R1 = OH R2 = (CH2)30H; derivative of BRL-6155 (Ref. [15]), compound 3, R1 = OH (equatorial) R2 = H; derivative of BRL-6155 (Ref. [15]), compound 4, RI = O R2 = H; derivative of BRL-6155 (Ref. [15]), compound 5, RI = OH (axial) R2 = H. The chosen c a n n a b i n o i d s were grouped into three categories, i.e.: 1. Group I: c o m p o u n d s from 1 to 5. Such c o m p o u n d s have an analgesic potency superior or equivalent to morphine; 2. Group H: c o m p o u n d s from 6 to 9. These compounds present an analgesic potency inferior to morphine; 3. Group III: c o m p o u n d s from 10 to 14. These compounds are inactive or present a very low analgesic potency.
D u r i n g the optimization process using the program PC M O D E L , special attention was given to some geometric parameters in the functional groups that confer
R1
Fig. 4. Derivative of 9-nor-9-/3-hydroxy-HHC,compound 6, R1 = OH (equatorial) R2 = OH R3 = OCH(CH3)(CH2)CrH6; Canbisol, compound 7, R1 = OH (equatorial) R2 = OH R3 = C(CH3)2(CH2)sCH3; derivative of 9-nor-9-/3-hydroxy-HHC, compound 8, R1 = OH (equatorial) R2 = OH R3 = CH(CH3)CH(CH3(CH2)4CH3; 9-nor9-/3-hydroxy-HHC,compound 9, RI = OH (equatorial) R2 = OH R3 = (CH2)4CH3; 9-a-hydroxy-&7-THC, compound 10 RI = OH (axial) R2 = OH R3 = (CH2)4CH3; 1l-hydroxy-A 9-THC, compound 11, RI = OH R2 = OH R = ( C H 2 ) a C H 3 ; derivative of 9-nor-9-/3hydroxy-HHC, compound 12, R 1 = OH (equatorial) R2 = COOH R3 = OCH(CH3)(CH2)3CrH6; derivative of 9-nor-9-B-hydroxy-HHC, compound 13, R1 = OH (equatorial) R2 = CH2OH R3 = OCH(CH3)(CH2)3CrH6; 9-nor-943-hydroxy-HHC, compound 14, RI = OH (axial) R2 = OH R3 = (CHz)aCH3.
S.L. da Silva et al./Journal of Molecular Structure 441 (1998) 97-100
99
Table 1 Optimized geometric parameters and analgisic activity for the cannabinoid compounds studied Compound number (See Figs. 2-4)
Distance between the oxygens (,~)
Torsion angle between rings A and C (degrees)
1 2 3 4 5 6 7 8 9 10 11 12 13 14
6.46 6.45 6.13 5.64 4.88 5.08 5.13 5.01 5.12 5.22 5.00 5.53 5.12 4.38
-150.77 -143.53 -116.41 -116.36 -136.54 -65.94 -68.98 -67.36 -67.10 -72.64 -67.12 -65.42 -68.99 -65.58
analgesia to the cannabinoid compounds, namely (see Fig. 1 for all cases): 1. the distance between the oxygen atom in the hydroxyl group of the A ring and in the phenylic ring (R1 and R2, respectively); 2. the torsion angle between the A and C rings defined by C5, C6, C l l and C10; 3. the torsion angle between the side chain R3 and the C ring, defined by C2, C3, C I ' , C2'. Table 1 gives the geometrical parameters found in our geometry optimization calucations for all compounds studied and in the last column we have outlined if the analgesic potency of the compound is superior or equivalent or inferior when compared with the analgesic potency of morphine, or even if the cannabinoid compound is inactive. From Table 1 we can see that the distance oxygen atoms of the hydroxyl group in the A ring and in the phenylic ring show some tendency for increased activity correlating with larger O - O distances. On the other hand, the torsion angles between the A and C rings defined by C5, C6, C11 and C10 present a more clear-cut correlation with the analgesic potency. Indeed, in Table 1, one can notice that if the torsion angle between the A and C rings is higher than 100 °, the analgesic potency of the cannabinoid will be
Torsion angle between ring C and the R3 chain (degrees) 133.38 132.10 125.32 122.60 136.65 123.20 110.96 112.93 110.28 88.61 89.01 92.49 92.43 79.00
Reported potencies (Ref. [13])
60-190 x morphine 8-25 × morphine 2 - 5 × morphine Similar to morphine Similar to morphine Potent Potent Potent Potent Some potency Some potency Low Potency Low potency Inactive
stronger or similar to the morphine. If this torsion angle is lower than 100 °, the cannabinoid can still present analgesic potency, but it will be lower than morphine, or even it will be inactive. In addition, for the torsion angles between the side chain R3 and the C ring in the cannabinoids studied, we can see that if the torsion angle is higher than 100 °, the compound will present at least an analgesic potency close to morphine. If the torsion angle is inferior to 100 °, the compound will present a very low analgesic potency, or even it will be inactive. ' It seems to be the combination of these two outcomes, the torsion angles between the A and C rings and between the side chain R3 and C ring give us some insight on the analgesic potency of the cannabinoid compounds studied here. If the torsion angles between the A and C rings and the side chain R3 and the C ring are both higher than 100 °, the compound will have a very strong analgesic activity (at least close to that presented by morphine). If the torsion angle between the A and C rings is lower than 100 °, but the torsion angle between the R3 and C rings is higher than 100 °, the compound will still present analgesic activity, but it will be inferior to the analgesic potency of morphine. If both torsion angles between the A and C rings and between the R3
100
S.L. da Silva et al./Journal of Molecular Structure 441 (1998) 97-100
and C rings are lower than 100 °, the c o m p o u n d will have a low analgesic activity, or it will e v e n be inactive. As a final remark, we ought to stress the qualitative character of our conclusions. It is clear that the potencies listed in the last c o l u m n o f Table 1 are qualitative. M o r e o v e r , Ref. [15] is a survey of several reports in which analgesic potency was meassured with different methods, Thus, what stands are critical g e o m e t r i c parameter values b e l o w or above which there is modification in analgesic activity.
Acknowledgements W e are grateful for financial support from F A P E S P , C N P q and F I N E P (Brazilian Agencies).
References [1] N.R. Farnsworth, J. Am. Pharm. Assoc. N59 (1969) 410. [2] C.E. Turner, M.A. Elsohly, E.G. Boeren, J. Nat. Products. 43 (1980) 169.
[3] Marihuana Research Findings, NIDA Research Monograph Series 31, U.S. Department of Health and Human Services, Rockville, MA, 1980. [4] J.A. Dill, A.C. Howlett, J. Pharm. Exp. Ther. 244 (1988) 1157. [5] S.H. Roth, P.J. Williams, J. Pharm. Pharmacol. 31 (1979) 224. [6] S. Burstein, S.A. Hunter, Biochem. Pharmacol. 27 (1978) 1275. [7] A. Makriyannis, S. Fesik, R. Kriwacki, in: A. Makriyannis (Ed.), New Methods in Drug Research, Prous, Barcelona, 1985. [8] A.B.F. da Silva, M. Trsic, J. Mol. Struct. 356 (1995) 247. [9] PC MODEL program (version 3.0), Serena Software, Bloomington, University of Indiana, IN 47402-3076, 1989. [10] MM2 (77) program, Quantum Chemistry Program Exchange Indiana, Bloomington, IN 47405, Program 395. [11] N.L. Allinger, J. Am. Chem. Soc. 99 (1977) 8127. [12] MMPI program, Quantum Chemistry Program Exchange Indiana, Bloomington, IN 47405, Program 318. [13] N.L. Allinger, J.T. Sprague, J. Am. Chem. Soc. 95 (1973) 3893. [14] A. Korolkovas, J.H. Burckhalter, Essentials of Medicinal Chemistry, Wiley, New York, 1976. [15] R.K. Razdan, Pharmacol. Rev. 38 (1986) 75. [16] A.C. Howlett, M.R. Johnson, L.S. Melvin, G.M. Milne, Mol. Pharmacol. 33 (1988) 297. [17] P.H. Reggio, K.V. Greer, S.M. Cox, J. Med. Chem. 32 (1989) 1630. [18] S.F. Semus, B.R. Martin, Life Sci. 46 (1990) 1781.