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Summary Background: From the deductive point of view, neurotransmitter receptors can be divided into categories such as cholinergic (muscarinic, nicotinic), adrenergic (α- and β-), dopaminergic, serotoninergic (5-HT1∼5-HT5), and histaminergic (H1 and H2). Selective agonists and antagonists of each receptor subtype can have specific useful therapeutic applications. For understanding the molecular mechanisms of action, an inductive method of analysis is useful. Objective: The aim of the present study is to examine the structure–activity relationships of agents acting on G-protein coupled receptors. Method: Representative sets of G-PCR agonists and antagonists were identified from the literature and Medline [P.M. Walsh (2003) Physicians’ desk reference; M.J. O'Neil (2001) The Merck index]. The molecular weight (MW), calculated logarithm of octanol/water partition coefficient (C log P) and molar refraction (CMR), dipole moment (DM), Elumo (the energy of the lowest unoccupied molecular orbital, a measure of the electron affinity of a molecule and its reactivity as an electrophile), Ehomo (the energy of the highest occupied molecular orbital, related to the ionization potential of a molecule, and its reactivity as a nucleophile), and the total number of hydrogen bonds (Hb) (donors and receptors), were chosen as molecular descriptors for SAR analyses. Results: The data suggest that not only do neurotransmitters share common structural features but their receptors belong to the same ensemble of G-protein coupled receptor with seven to eight transmembrane domains with their resultant dipoles in an antiparallel configuration. Moreover, the analysis indicates that the receptor exists in a dynamic equilibrium between the closed state and the open state. The energy needed to open the closed state is provided by the hydrolysis of GTP. A composite 3-D parameter frame setting of all the neurotransmitter agonists and antagonists are presented using MW, Hb and μ as independent variables. Conclusion: It appears that all neurotransmitters examined in this study operate by a similar mechanism with the G-protein coupled receptors.

Summary Objective: A large number of structurally and functionally diverse compounds act as substrates or modulators of p-glycoprotein (p-gp). Some of them possess multiple drug resistance (MDR)-reversing activity, but only a small number of them have entered clinical study. In order to uncover the factors which exert a significant impact on the interaction between substrates/modulators and p-gp, we have performed structure–activity relationship (SAR) analyses, including molecular modelling, two-dimensional (2D) and three-dimensional (3D) parameter-frame-setting analysis, quantitative structure activity relationship (QSAR) analysis among substrates/modulators, as well as clinically promising MDR-reversing agents. Methods: The physicochemical parameters C log P, CMR and all regression equations were derived by using C log P version 4·0 and the latest CQSAR software, respectively. Molecular modelling and all other parameter calculations were performed by using HyperChem version 5·0 program, after geometry optimization and energy minimization using the AM1 semiempirical method. Results: SAR analyses indicate that MDR reversal activity is correlated with the lipophilicity (C log P), molecular weight (log Mw), longest chain (Nlc) of the molecule and the energy of the highest occupied orbital (Ehomo). In addition, the presence of a basic tertiary nitrogen atom in the structure is also an important contributor to p-gp inhibitory activity. Some separation in space is achieved for different subsets of p-gp substrates and inhibitors using Nlc, C log P and Ehomo as three independent parameters in the 3D-parameter-frame setting. Conclusion: A highly effective p-gp modulator candidate should possess a log P value of 2·92 or higher, 18-atom-long or longer molecular axis, and a high Ehomo value, as well as at least one tertiary basic nitrogen atom. The results obtained may be useful in explaining drug–p-gp interactions for different compounds, including drug interactions and the development of new MDR chemosensitizers.

Seven ellagitannins isolated from Phyllanthus myrtifolius and P. urinaria (Euphorbiaceae) have been shown, for the first time, to be active against Epstein-Barr virus DNA polymerase (EBV-DP) at the microM level. All these compounds have the same moiety of a corilagin, and differ from each other by different substitutions at C-2 and C-4 of the glucose core. SAR analysis and molecular modeling reveal that the essential pharmacophore of these tannins resides in the corilagin moiety. The outer complex carboxylic acid moieties appear to act only as auxopharmacore.

The theoretical basis of stereoselectivity in drug targeting in terms of eudismic ratio and quantitative structure-activity relationship has been presented. Specific examples of the advantages of using the correct stereoisomers (eutomers) rather than the distomers or racemic mixtures have been discussed. With the recent development of new methods of chiral synthesis and chiral analysis, it is not longer justifiable to continue to use racemic mixtures as therapeutic agents, unless it can be proven to be safe to do so. In the area of using peptides, proteins, glycoproteins and polysaccharides as therapeutic agents, mother nature has been very selective in choosing the optically active starting materials (Bradley, 1994), it is a necessity to design and test the proper optical isomer when a mimetic or antagonist compound is contemplated as a therapeutic agent.

In view of the increasing number of patients undergoing kidney dialysis or transplant every year, a survey of the literature on renal protective medicinal plants was undertaken. Most of them are from traditional Chinese medicine (TCM). Although many of the medicinal herbs reported have not been investigated in terms of active chemical ingredients, some do have compounds well characterized. They fall into a wide range of structures. Several groups of compounds with well established activities are discussed. These include: antioxidant phenolic compounds like tannins, flavonoids, isoflavonoids, unsaturated organic acids and lignans; circulation enhancing compounds like saponins, and basic alkaloids with multiple targets (G-protein coupled receptors). Also presented are proinflammatory and antiinflammatory fatty acids like linoleic (n-6) and α-linolenic (n-3) acids, respectively. Attention is also drawn to the plants containing nephrotoxic aristolochic acid. Different directions of future research are also presented. We hope that this review may provide some leads for new drug discovery and development, and more rational application of TCM.

Acquired immunodeficiency syndrome (AIDS) is an immunosuppressive disease characterized by an immune impairment and a high susceptibility to unusual forms of certain neoplasms. Since the brain is an important site of the infection, it is necessary to explore new classes of drugs that have the ability to penetrate across the blood–brain barrier, and the potency to suppress viral replication within the central nervous system (CNS). Therefore, the ability to predicate the lipophilicity of the potent anti-AIDS drugs may provide useful information about the potential of the drugs to enter CNS. In this paper, the correlations of log P (octanol-buffer partition coefficient) and log f R (retention time in HPLC; R , was used by Balzarini et al.) with some physical constants like log MW (molecular weight), hydrogen bond forming ability (HB) of the substitu- ents, and the substituent group dipole moments (s) are analyzed. Good correlations of log P and log f R with log MW, HB, and s have been obtained.

Combretastatins and their synthetic analogues, having structural features resembling that of colchicine, also have similar modes of action. In this report we have correlated the cytotoxicity of combretastatins against the murine leukemic cell line L1210 with physicochemical parameters such as the summation of the Hansch-Fujita pi constant, which was used as an index of lipophilicity of the substituent groups on ring A (sigma pi a) and ring B (sigma pi b), the vector summation of the group dipole moments of ring A (sigma mu a) and ring B (sigma mu b), the nature of the linker chain between ring A and ring B (Bt-L), indicator parameters (NOH)a and (NOH)b, which represent the number of hydroxyl groups on ring A and ring B, respectively, and the summation of pi values of the substituents on the linker (sigma pi L). Cytotoxicity correlated well with (sigma pi b), (NOH)a, (Bt-L), and (sigma mu b), and the dependency on (sigma pi b) was found to be parabolic.

A series of N-hydroxy-N'-aminoguanidine (HAG) derivatives were studied and compared for their effects on ribonucleotide reductase activity in cell-free extracts; on nucleic acid synthesis and the growth of human colon carcinoma HT-29 cells; and on mouse leukemia L1210 cells in culture. The HAG derivatives [RCH=NNHC(=NH)NHOH-tosylate] studied could be grouped as: (1) hydroxybenzylidines; (2) methoxybenzylidines; and (3) nitrobenzylidines substituted at the R position. 2'-Hydroxybenzylidine-HAG, the lead compound, was relatively active in both HT-29 cells and L1210 cells (20 +/- 5 and 13 +/- 4 microM for 50% inhibition of HT-29 and L1210 cell growth respectively). The monohydroxybenzylidene compounds were generally more active than the dihydroxy- and trihydroxybenzylidene-HAG derivatives. The methoxybenzylidene-HAGs were as active as the monohydroxybenzylidene-HAGs. 2'-Hydroxy-4'-methoxybenzylidene-HAG was much more active than 2',4'-dihydroxybenzylidene-HAG. The mononitrobenzylidene-HAGs were more active than the dinitrobenzylidene-HAG compound. In general, L1210 cells were more sensitive to the effects of the HAG compounds than were HT-29 cells. There was good agreement between the concentration of drug required to inhibit the growth of HT-29 cells and that required to inhibit the growth of L1210 cells. There was also good correlation between the ability of HAG derivatives to inhibit ribonucleotide reductase activity and to inhibit tumor cell growth. Some derivatives, such as 2',3',4'- and 3',4',5'-trihydroxybenzylidene-HAG inhibited L1210 cell growth by 50% at lower concentrations (7.8 and 11.9 microM respectively) than the concentrations needed for 50% inhibition of HT-29 cell growth (196 and 234 microM respectively) and ribonucleotide reductase activity (122 and 188 microM respectively). The studies of nucleic acid synthesis in L1210 cells using [3H]cytidine as a precursor showed that 2',3',4'-trihydroxybenzylidine-HAG inhibited DNA synthesis at a lower concentration (29 microM for 50% inhibition) than was needed for the inhibition of RNA synthesis and formation of [3H]deoxycytidine nucleotides in the acid-soluble fraction (320 and 820 microM for 50% inhibition respectively). These results indicate that 2',3',4'-trihydroxybenzylidine-HAG inhibits DNA synthesis in L1210 cells through other mechanisms rather than exclusively through the inhibition of ribonucleotide reductase activity.

Further modifications of the structural features of Schiff bases of hydroxyaminoguanidines (SB-HAG) led to nine substituted salicylaldehyde Schiff bases of HAG (SSB-HAG) derivatives and three other SB-HAG derivatives. These new compounds were tested for the first time against infection by a coronavirus, mouse hepatitis virus (MHV). The most active compound, 2 [1-[(3'-allyl-2'-hydroxybenzylidene)amino]- 3-hydroxyguanidine], against the growth of MHV is about 376 times more active than hydroxyguanidine and about 564 times more active than HAG itself when the TCID50 values are compared. Plaque assays of MHV released from cells treated with these compounds suggest that SSB-HAG tosylate may inhibit the transcription of viral RNAs in virus-infected cells. Quantitative structure-activity relationship (QSAR) analyses of two subsets show that the inhibitory activities correlate well with the electronic and the lipophilic parameters. The structural requirements for the antiviral activity of substituted SSB-HAG tosylate against coronaviral infection are stringent according to the inhibitory activities and QSAR analysis of these new compounds.

Characterization of the cell cycle has introduced CDKs and other proteins as possible targets for inhibition of cell proliferation, such as, CDK1 and CDK2, whose inhibition may be useful in the treatment of proliferative disorders. Structure-activity analyses have been instrumental in the design and discovery of potent CDK inhibitors, such as purine analogs, which have increased in potency from the micromolar to the nanomolar level. X-ray crystallography and molecular modeling have provided evidence that these compounds act on the CDK target enzyme. Selected CDK inhibitors have successfully entered clinical trials. Further characterization of the cell cycle to identify molecular targets to inhibit cell proliferation, QSAR and SAR studies, and clinical trials may expedite the development of CDK inhibitors for therapeutic use.

In this report, the quantitative structure-activity relationship (QSAR) analyses of substituted phenols, vitamin E derivatives and flavonoids are presented. Two models have been derived using calculated parameters such as the heat of formation (Hf), the energy of the lowest unoccupied molecular orbital of radicals (E(lumo-r)) the energy of the highest occupied molecular orbital of the parent compounds (E(homo)) and the number of hydroxyl groups (OH). These models can be used to estimate the redox potentials or antioxidant activities of new substituted phenolic compounds or vitamin E derivatives. The Trolox equivalent antioxidant capacities (TEACs) of 42 different flavonoids are found to be mainly governed by the number and location of hydroxyl groups on the flavonoid ring system.

A general mathematical model involving partition coefficient, molecular weight and hydrogen bonding is used to correlate the structures and permeability of various organic compounds through the toad urinary bladder and human red blood cell (RBC) membranes. Log Per (permeability) is correlated with log Po/w (partition coefficient in olive oil/water, or ether/water), log MW (molecular weight) and Hb (hydrogen bonds). Log Po/w is the most important factor among three parameters examined. While increased MW always has a negative effect on the permeability, increased Hb can have either a slightly positive or a slightly negative effect depending on the solvent and membrane systems used. Systematic comparison of the QSAR's (quantitative structure activity relationship) of different biological membranes may serve as a useful guide in drug targeting to different tissues and cell types.

In the search for new brain imaging agents for the use with single photon emission computed tomography (SPECT), quantitative structure activity relationship (QSAR) analysis of the correlations between initial brain uptake and physicochemical parameters like lipophilicity, log P, molecular weight, log MW and log U/D (undissociated/dissociated), of the 99mTc-DADT (diaminedithiol) complexes and 99mTc-PAO (propyleneamineoxime) complexes have been analyzed. High correlations are found for both the 99mTc-DADT complexes (r = 0.94) and for the 99mTc-PAO complexes (r = 0.83) which are significant at 99.9 and 99.5 percentile level, respectively. These results will help the further design of better ligands for 99mTc in brain imaging.

The relationships between 210 aliphatic group dipole moments (mu) and Taft polar constants (sigma *) are explored, and they are shown to be correlated by a general equation: mu = -a X sigma * -b X n' -c, where a, b, and c are constants. The value n' is a parameter reflecting the attenuating factor due to the number and electronic nature of the interval atoms between the most electronegative atom and the first atom connected to the acetate in the measurement of sigma *. The mu and sigma * values of over 214 aliphatic substituents are compiled for future correlation studies. Comparative examples using sigma * and mu in quantitative structure-activity relationships are presented.

The theoretical basis for using dipole moment as a free-energy related parameter in studying drug-receptor interaction and quantitative structure-activity relationship (QSAR) is presented. Over 300 group dipole moments for aromatic substituents were compiled using the dipole moments of monosubstituted benzene derivatives. Examples in the literature of using dipole moment in QSAR studies are also presented.

Hydroxyurea, hydroxyguanidine, and some thiosemicarbazones have been shown to have anticancer and antiviral activities. One of their possible sites of action is the enzyme ribonucleotide reductase (RR). Combination of the structural features of these compounds led to the design and synthesis of the Schiff bases of N-hydroxy-N'-aminoguanidine. Synthesis and structure-activity studies of some of these compounds point to increased size and lipophilicity as important factors for activity. To optimize the activities of this series of compounds, 13 derivatives of high lipophilicity and molecular size have been synthesized and their biological activities studied. The most active anticancer compounds against L1210 in vitro (compounds 9 and 12) are about 7 times more active than hydroxyguanidine and hydroxyurea. The most active antiviral compounds against Rous sarcoma virus transformation of chick fibroblasts in vitro (7, 9) are about 40 times more active than hydroxyguanidine. One of the compounds (4) shows promising activity in vivo (% T/C = 140 against P388 leukemia in mice) and is undergoing further studies by the National Cancer Institute (NCI). Studies of the inhibition of transformation of chick embryo cells by Rous sarcoma virus show that all these compounds inhibit transformation while some compounds inhibit viral replication as well.

A list of 37 anticancer drugs with reported carcinogenicity or co-carcinogenicity has been compiled. These drugs include 16 alkylating agents, eight antimetabolites, four antibiotics, four hormones, one alkaloid, and four miscellaneous drugs. The reported carcinogenicity of these drugs in model systems and their possible mechanisms of action are reviewed together with structure-carcinogenicity relationships. These drugs have been reported to cause cancers in different sites in various test animals. Most of these drugs react with DNA, and the ultimate reactive forms of the drugs are electrophiles.

In previous studies, N -hydroxy- N ′-aminoguanidine (HAG) derivatives were demonstrated to suppress growth and clonogenicity of tumor cells which correlated with the inhibition of ribonucleotide reductase and DNA synthesis. The present work has focused on the properties of five HAG derivatives as inhibitors of the ribonucleotide reductase from Ehrlich ascites tumor cells. HAG derivatives acted as non-competitive inhibitors of ribonucleotide reductase with respect to the substrates CDP and ADP. The apparent K i , values for the various HAG derivatives as inhibitors of CDP reductase ranged from 3.4 to 543 μM. However, the apparent K i values for these inhibitors with respect to ADP reductase were 2- to 10-fold lower than the respective values for CDP reductase. After a preincubation of HAG derivatives and ribonucleotide reductase in the absence of substrates, an increased inhibition was observed. The activity of the inhibited enzyme could be restored by passage over a Sephadex G-25 column and subsequent incubation with dithioerythritol. The addition of either the non-heme iron subunit or the effector-binding subunit to the intact enzyme in the assay mixture resulted in a diminished inhibition of ADP reduction. Inhibition by HAG derivatives of ribonucleotide reductase activity in the test tube was not enhanced by iron chelators. However, a combination of HAG compounds and iron chelators synergistically inhibited the growth of L1210 cells.

SUMMARY It is shown by means of regression analysis that the lipophilic character of the molecule as expressed by log P in octanol/water is very important in determining the relative activities of these compounds in all of the three systems examined. In addition, molecular weight is also important in some of the systems. In general, activity increases with increasing lipophilicity and molecular weight for the limited number of compounds studied. The role of degree of ionization of these acidic drugs may affect both penetration and intrinsic activity in different ways. The finding by Sheu et al., (1) that long-chain fatty acids inhibit gram-positive bacteria (Bacillus subtilis) but not gram-negative bacteria such as E. coli, due to the protective layer of lipopolysaccharide, is in agreement with the correlations obtained for many different series of antibacterial agents by Lien, Hansch & Anderson (2).

A study was conducted in which the same organic solvent, 1-octanol, and different buffer systems were used to obtain intercorrelations among log Pcorr values given by log P (octanol-water) = a log P (octanol-buffer) + b, where a and b are different constants for the different systems used. The range of a was 0.418-1.156 and that of b was -1.962-1.176 for the four buffer systems examined. Only with neutral drugs was the slope (a) close to 1.0 and the intercept (b) close to 0.0 for the three buffer systems studied. For acidic drugs, only 1-octanol-phosphate buffer gave a 1:1 correlation with 1-octanol-water partition coefficients. Acetate and bicarbonate buffer systems gave different correlations. For basic drugs, none of the three systems examined gave a 1:1 correlation with 1-octanol-water partition coefficients.

A series of 16 derivatives of 2-hydroxy-1H-isoindole-1,3-diones was designed and synthesized as potential antitumor agents. The cytostatic activity against L1210 cell growth of these compounds was studied, and their IC50 values were found to be in the range of 10(-4) to 10(-8) M. Quantitative structure-activity relationship analysis of these compounds showed that the inhibitory effect was well correlated with the electronic and the lipophilic parameters. Derivatives having a substituent with strongly electron-donating properties at the 6-position showed enhanced inhibitory activity while compounds having an electron-withdrawing group at the same position showed lower activity.

The work of Hall on the correlation of base strengths of aliphatic amines using Taft's polar constant, σ∗, has been extended. It has been shown that the pKa values for 92 amines can be correlated in a single two-parameter equation using σ∗ and nH, where nH indicates the number of hydrogen atoms on the protonated amino nitrogen. This relation can then form the basis for correlating chemical structure and biological activity of amines. In this paper the antagonism of adrenaline, noradrenaline and 5-hydroxytryptamine (5-HT) by a variety of 2-bromo-2-phenylalkylamines is considered. It is shown that substitutents on the aromatic ring are involved in hydrophobic bonding, while those on nitrogen do not seem to influence the biological activity in this fashion. The function of the nitrogen substituents appears to be limited to that of regulating the availability of the lone-pair electrons for immonium ion formation and for its reactivity. The compactness of the nitrogen substituents is shown to be necessary for high adrenergic blocking activity. Possible ways of molecular modification for more active compounds are suggested.

A computerized sorting program was used to sort out 120 drugs that have been reported to cause skin sensitization from a data bank of 540 clinically useful drugs. Based on an analysis of functional groups, a number of unique common denominators were found for skin sensitization due to covalent bond formation with body proteins. These include potential epoxide-forming groups such as an electron-deficient benzene ring, a vinyl group, hydroxylamine and N-oxide precursors, drugs capable of forming a benzylic radical, β-lactam derivatives, and α,β-unsaturated ketones. By using multiple-regression analysis, the quantitative structure–activity relationship for skin-sensitizing properties of 3-alkyl catechols and 2,4-dinitrobenzene derivatives are also reported.

The anticonvulsant and CNS-depressant activities of 16 commercially available antiepileptics were subjected to regression analysis. For the maximal electroshock seizure test and pentylenetetrazol seizure threshold test, good correlations were obtained only after diazepam, clonazepam, and carbamazepam were deleted; for the median toxic dose (rotorod ataxia), all 16 compounds can be included in one single equation using log MW, log P, and dipole moment ( μ ) terras. For the anticonvulsant activities of 7-substituted 1,4-benzodiazepinones, a parabolic equation of π combined with the Hammett σ constant gave fair correlations for most derivatives examined in three different tests. Based upon the correlations obtained, further molecular modifications are suggested. The dipole moments of seven clinically used antiepileptic drugs were measured in 1,4-dioxane for the first time.

Group theory was applied to a wide variety of toxic substances, drugs, and endogenous organic compounds to test the apparent empirical relationship between toxicity of a molecule and its degree of molecular symmetry. Many compounds in each classification were analyzed and separated into individual symmetry groups using “space-filling” molecular models. With few exceptions, an apparent relationship was noted between each symmetry group and the relative toxicities. A brief introduction to group theory is presented as well as the rationale and implications of these observations.

Hydroxyguanidine contains both features of guanidine and hydroxyurea and has antiviral and anticancer activities both in vitro and in vivo. In order to enhance the antiviral and anticancer activity of this compound, a new series of hydroxyguanidine derivatives with the following structures were synthesized: R = NNHC(= NH)NHOH, where R = aromatic or heterocyclic aldehyde. This series of compounds was prepared in order to alter the lipophilic/hydrophilic balance, as well as the electronic and steric properties of hydroxyguanidine. The anticancer activities of the compounds were tested against cultured L1210 cells. The ID50 values of the above compounds are in the range of 7.80-126 microM. They are about 10-fold more active than hydroxyurea and hydroxyguanidine. The antiviral activities were also tested by assaying the inhibition of transformation of chicken embryo fibroblasts infected with Rous sarcoma virus. The ID50 values of these new compounds are in the range of 2.76-195.2 microM. The most active ones are about 100-fold more active than hydroxyguanidine. At the ID50, no apparent toxicity to the cells was noticed.

Breast feeding has increased by approximately 25% in the United States during the past decade and this trend appears to be continuing. The number of drugs available to lactating women is also growing at a rapid pace. The excretion of drugs into breast-milk presents a potential danger to infants. In spite of this, little is known about the excretion of drugs into breast-milk. The ability to predict which drugs are potential hazards would be very useful in the clinical setting. This study quantitatively correlates the human milk to plasma concentration ratio of various basic and acidic drugs (log M/P) with the square root of the molecular weight, the partition coefficient (log P) and the degree of dissociation (log U/D). For basic drugs there is a negative-dependence on both log P and log U/D. High lipophilicity favours protein binding and reduces the amount of drug available for diffusion into milk. Therefore, as log P increases, the log M/P decreases. The negative-dependence on log U/D indicates that the higher the degree of dissociation of the base in plasma, the greater the log M/P will be. This fits well with the concept of ion-trapping. A strong base is more likely to be transferred and then trapped in milk which has a lower pH than plasma. For acidic drugs there is a negative-dependence on both square root (MW) and log P. The negative-dependence on square root (MW) suggests that large molecules are less likely to be able to diffuse into the milk. A negative-dependence on log P appears to hold true for bases and acids. Log M/P decreases as log P increases. This is probably due to increased protein binding by lipophilic drugs through non-specific hydrophobic interaction with plasma protein.

The effect of molecular weight on drug diffusion and drug action has been described based on the relation D = (RT/6 pi eta N) (cube root of (4 pi N divided by 3M nu-), an inverse relation between the clearance of drugs through artificial membranes and molecular weights, and apparent correlations between log (l/dose) and log mol. wt. for various central nervous system-acting drugs, anticancer drugs, and water-soluble vitamins. In situ rat jejunum permeability data of various drugs were correlated with log P (octanol-buffer) and log mol. wt. A parabolic equation of log P combined with log mol. wt. proposed previously was shown to give significant correlations for hydrolysis data of amides and antifungal data of amines. This model is mathematically simpler and easier to interpret than the more complex curvilinear and bilinear models.

Various CNS activities, such as antielectroshock, antipentylenetetrazol-induced seizures, muscle relaxant, and acute lethal toxicity, of different types of compounds were correlated with three physicochemical parameters, namely lipophilicity (log P), dipole moment, and steric considerations (Es). The relatively narrow range of log P0(2.0 ± 0.7) for compounds possessing a polar group, e.g., amido, thioamido, keto, or alcoholic function, strongly suggests that the rate-limiting step for these different CNS-acting drugs is probably the same, namely the penetration of the tightly packed neuroglial cells (the so-called blood-brain barrier). Negative dependence of the anticonvulsant or CNS depressant activity on the dipole moment and positive dependence of the stimulatory CNS toxicity on the same parameter were found to be statistically significant. Entirely different sites and mechanisms of action appear to be evident from the very low estimated log P0 values of lactones and 2-sulfa-moylbenzoates for their CNS depressant activities. The CNS activity of five lactones was studied in mice. While γ-butyrolactone caused dosage-dependent sedation and sleep at 100–1000 mg./kg., no loss of the righting reflex was observed for α-methyl-γ-butyrolactone (1000 mg./kg.), γ-valerolactone (2000 mg./kg.): γ-valerolactone (750 mg./kg.), and γ-heptalactone (1000 mg./kg.). After intraperitoneal injection of γ-valerolactone and γ-heptalactone, paralysis of the hind legs was observed, indicating local anesthetic activity on the peripheral nervous system.

Data presented show that lactams, which have the resonating structure commonly associated with CNS depressants and CNS stimulants, have significant CNS activities. Results of preliminary testing show that lactams of medium ring size and lacking N-substitution are fairly potent CNS stimulants. The acute lethal toxicity (log 1/C) of four CNS stimulants of the lactam type is found to be highly correlated with log P, where P is the 1-octanol-water partition coefficient for the compound. The rate of respiration in mice depressed with sodium pentobarbital is stimulated by 2-azacyclononanone, and the rate and depth of respiration were increased by 2-azacyclooctanone in dogs anesthetized with sodium pentothal. Both 2-azacyclooctanone and 2-azacyclononanone are capable of reducing considerably the sodium pentobarbital sleeping time in mice. At higher doses, the CNS stimulant effects of these drugs are manifested by convulsions. For 2-azacyclooctanone, the convulsant ED50 is about 37 mg./kg. and the LD50 is about 300 mg./kg. Direct evidence for CNS stimulation by 2-azacyclooctanone was obtained by recording changes in EEG patterns in artificially ventilated dogs paralyzed with d-tubocurarine. Diphenylhydantoin is much less effective as an antagonist to the convulsant actions of 2-azacyclooctanone than sodium pentobarbital. This finding, taken together with the tonic-clonic convulsions produced by this drug, strongly suggests that, like nikethamide and pentylenetetrazole, the site of action for its CNS effects is subcortical and supraspinal. The conclusion is drawn that the resonating moiety shown here confers upon many compounds CNS-stimulant activities.

A computer program using PL/I language was developed to sort the side effects of 540 clinically useful drugs. The common structural features of the drugs that produce the extrapyramidal syndrome are: (a) the drug contains at least one tertiary amino group separated by three carbon atoms from a coplanar hydro-phobic region, and (b) the coplanar hydrophobic region can be a phenothiazine ring, its isosteres, or two benzene rings held close together (e.g., trimethobenzamide and haloperidol). Other tran-quilizers and anticonvulsants such as diazepam and diphenyl-hydantoin are shown to have entirely different structural features.

The micelle formation tendency (log 1/CMC)) of a series of alkyldimethylbenzylammonium compounds is shown to be linearly dependent on the alky chain length, indicating no curling of the side chain up to C19. Protein binding of these charged molecules on the primary binding site for sulfaethiodole is shown to be parabolically dependent on the chain length with an optimal chain length around C16.