药物化学构效关系（Pharmacochemical structure-activityrelationship）barbituratesBarbiturates are structural nonspecific drugs.Structure nonspecific drugs: the biological activity of the drug is not related to the chemical structure of the drug.Structural specific drugs: the effects of drugs depend on the specific chemical structure and spatial alignment of drug molecules.The function of barbiturates and the fast and slow time of the drug are closely related to the dissociation constant, PKa, and the distribution coefficient of lipid water.Dissociation constant: the drug ACTS as an ion in the form of molecules through the biofilm.Oil and water distribution coefficient: the drug can be transported both in body fluids and through the blood-brain barrier.The category 5 is active, there are two substituents on the total number of carbon atoms when two substituent between 4 to 8, the distribution coefficient is moderate, active best. When the total number of carbon atoms in more than eight, effect is strong, easy to produce convulsion. The structure of the N atoms on the methyl on the imide replaced can reduce acidity andincrease the fat soluble, work fast. Use of C - 2 O S alternative. Increase lipid solubility and easy through the blood brain barrier, it works fast.The metabolism of barbiturates is associated with the metabolic time of the drug.2. Benzodiazepines (diazepam)A ring is necessary for the activity.B ring can be replaced by other aromatic rings, and it retains its activity.One is generally n-ch3. - CH3 can be removed in metabolism, but retains its activity1.2 bits can be added to the heterocyclic ring (triazolam: increased stability and increased activity)Three of the H atoms can be reduced slightly by -oh, but very low toxicity.4, 5 for the double bond to be saturated. The activity decreases, and incorporation into oxazole to increase sedation and antidepressant effect.The 2 bits of 5 - phenyl are introduced into the electron base (F, Cl, Br...). Increased activity.7 bits were introduced into the electron base, and the activity significantly enhanced NO2 > CF3 > Br > Br > ClThree. Aryl propionic acid (ibuprofen)One or more carbon atoms are spaced between a benzene ring and a carboxyl group.The carboxyl group of a is another - CH3, which limits the free rotation of carboxyl group, keeping it fit for the binding of the receptor or enzyme to increase the anti - inflammatory analgesic effect.Because of carboxyl a bit - the introduction of CH3, make its produce the asymmetric center, is usually a S - configuration activity is higher than R - configuration, can mutual transformation between chiral isomers in the body, is normally inactive R - S - configuration into active configuration.Another hydrophobic base, cyclohexyl and allyl oxide, can be introduced in the aromatic ring.The interposition of benzene ring carboxyl group is introduced into a suction electron base such as F.C l, etc.Anti-inflammation activity is good.Iv. The constitutive effect of cholinergic receptor agonists (choline choline)Positively charged amino 1, quarter. (1) the nitrogen atom is must be active. If the As, Se replace activity. (2) methyl instead As well on the nitrogen atoms, if replace with larger groups such As ethyl activity decreased, if three ethyl into choline active resistance.2 acetoxyl group. (1) when the acetyl or butyl acyl replace activity, (2) on the acetyl hydrogen is replaced by aromatic ring or larger groups to fight choline activity. (3) the rapid hydrolysis of ester base for acetylcholine effect time short and unstable factors, so it not easy to replace acetyl groups can increase the stability of the hydrolysis and action time. Such as acetyl ammonia formyl replaced, because in the nitrogen lone pair electrons, carbonyl carbon is electrophilic acetyl is low, not easy to hydrolysis.3, ethylidene bridge. (1) ethylidene has key influence on activity of the length of the bridge, two carbon for the best. With the extension of carbon chain, the activity is gradually reduced. (2) the quaternary ammonia nitrogen atom of a bit have replaced by methyl, overall activity decreased, but lack of the sample N greater than M. (season 3 of ammonia nitrogen atom B have replaced by methyl, can prevent the effect of cholinesterase, extend the action time, effect on the acetylcholine M sample, sample N effect greatly abate, be selective M receptor agonist.The constitutive effect of adrenal receptor agonistThe basic structure of phenylethylamine is the activity and the elongation or shortening of the carbon chain reduces the effect.Phenol hydroxyl groups in benzene ring significantly enhanced the role of pseudo adrenalin, especially in the 3 or 4 digits, but the effect time was brief.The peripheral function was retained and the central excitation decreased.N substituent on the relative strength of a and B receptor effect have a significant impact. The alternative to base from methyl tert-butyl, a receptor effect weakened. B receptor effect increase, and the selective increase of B2 receptor.B - carbon usually has hydroxyl group. Its absolute configuration is R - configurational.The constitutive relationship of anesthetics.The adjacent position gives the electron base substitution, which is beneficial to the formation of the amphoteric ion and the activity is enhanced. If there is an electron absorption, the activity decreases.It can be aromatic ring, aromatic heterocyclic, the modification of this part has a great influence on the activity, the active sequence is the benzene ring > pyrrol > furanIt's usually best to have 2 or 3 carbonsThere are secondary amine, tertiary amine or pyrrolidine, piperidine, etc., and tertiary amine is the most common.Insert - CH2, between benzene ring and carboxyl - O - groups, such as damage to the formation of zwitterionic. Activity. If connected to conjugate groups can be formed, such as - CH2 =CH2 -. Activity can remain the same. Amide also can form the amphoteric ion.In this part, the stability of the drug is determined, and the time sequence of carbonyl + -o->... + - S - >... + - NH - >... + - CH2 -; The order of strength: -s-> - o->-ch2 - > - NHThe constitutive relationship of beta blockers (figure of figure).Phenylethanolamine and aromatic propanolamineIt can be benzene, naphthalene, heterocyclic, dense ring, and fatty unsaturated heterocyclic. It can be substituted for methyl, chlorine, nitro, methoxide, etc., with the best activity in 2, 4 and 2, 3 and 6 positions.When substituted with S, CH2, -nch3, the activity decreases.The activity of s-configurational isomers increased, and the activity of r-configurational isomers decreased or disappeared.The activity of r-configurational isomers increased, and the activity of s-configurational isomers decreased or disappearedTertiary butyl and isopropyl instead at best, the hydrogen atoms on the methyl for less than 3 or N - N double replaced, activity decreased. Due to the structure of great B receptor blockers, so its solubility also have bigger difference, which related to its side effects and the location of the positionto eliminate. Pro fatty liver metabolism - rate faster. The hydrophilic - renal eliminationStructure-effect relationship of dihydropyridine drugs (nifedipine)The activity of dihydropyridine ring is necessary for the activity. If the activity of pyridine ring or hexahydropyridine ring is lost, the NH in the ring is not replaced, and the activity remains the best.2, 6 substituents are low - grade alkanesThe 3, 5 carboxylic acid lipid is necessary for the activity, and if it becomes acetyl or cyano, the activity decreases, and if it becomes nitro, the calcium channel can be activated.The 3, 5 carboxylic acid is different, the C4 is chiral center, the size of the ester group has little influence on the activity, but the asymmetric fat affects the part.C4 is stereoscopic for chiral carbonThe relationship between the four substituents and the activity: phenyl or substituted phenyl > ring alkyl > methyl > HIn the adjacent Spaces of the benzene ring, there is a better activity of the electron base substitutionThe constitutive effect of H2 receptor antagonist (ranitidine).The structure of the H2 receptor antagonist consists of three parts: the basic aromatic ring structure, and the four atomic chain and the polar group.Alkaline aromatic heterocyclic and alkaline groups substituted aromatic heterocyclic are necessary to active, imidazole ring as the proton transfer mechanism, by different thiazole, pbo replacement after alkaline, activity also decreases. By lipophilic aromatic heterocyclic (benzene) replaced activity. Was replaced by the alkaline groups, furan, thiazole, after displacement is good H2 receptor antagonist.Planar polar groups. It is the structure of guanidine and amidine. In the physiological PH condition, the polar groups with low ionization degree can form more than one hydrogen bond with the receptor forming one of the hydrogen bonds.The chain length is 4 atoms long. The chain length is related to antagonism. Free rotation and restriction make its activity fall, and the chain of intermediate connection can be replaced by the steel ring.The constitutive effect of penicillin(1) six side chain of amide groups mainly decided its antibacterial spectrum, change its polarity, makes it easy to through the cell membrane, can enlarge its antibacterial spectrum. For example, in a place of aromatic ring ethyl amide group introduced polarity - NH2, - COOH, - SO2 hydrophilic groups, such as antibacterial spectrum. Increase thehydrophilicity. Is advantageous to the bacteriostatic action of bacterium of negative of glen, and can enhance the affinity of binding protein to penicillin.The position of the three-dimensional resistance group is introduced in the appropriate position of the molecule.As in the side chain is introduced into the three-dimensional steric larger groups and introduced in six methoxyl and formamide, because of its three-dimensional steric effect reduces the passivation enzyme structure adaptability, protect B - lactam ring from B - lactamase attack. So get resistance to antibiotics of enzyme.Penicillin thiazole ring of carboxyl is basic reactive group, although can be replaced by sulfur acid and amide activity. If the reduction of carboxyl of alcohol, antimicrobial activity was lost. For fat carboxyl made available before the medicine principle, improve the oral absorption and pharmacokinetic properties.The configuration of three chiral carbons in penicillium is essential for its activity, but the two methyl groups on the thiazole ring of penicillin are not necessary for the activity.The constitutive effect of semi-synthetic cephalosporinIn seven side chain introduction of lipophilic groups, such as phenyl, dilute base, thiophene and nitrogen heterocyclic. Can be enhanced antibacterial activity, expand its antibacterial spectrum. Change 3 substituent at the same time, theintroduction of heterocyclic, can improve the oral absorption distribution also can expand its antibacterial spectrum.A position of 7 amides was introduced into the hydrophilic - SO3H, -nh2, -cooh, isopolar group. The antibacterial spectrum could be expanded to change 3 substituents, and the introduction of -cl, CH3, and nitrogen-containing heterocyclic could enhance oral absorption and expand the antibacterial spectrum.With 7 B as the side chain of ammonia oxime "conveniently" can improve the stability of B - lactamase, expand the antibacterial spectrum. This is mainly due to the introduction of oxime, methoxy occupy the position near the B - lactam ring. Prevents the enzyme molecules of B - lactam ring close to, so that drug resistant enzymes, the nature of broad spectrum.5 S with biological electronic body O, CH2, etc, respectively called cephalosporins cephalosporin and carbon, oxygen activity is not reduced. 3 substituent of transformation, such as acetoxyl group can be methyl, chloride to replace you can expand the antibacterial spectrum and change the absorption of drug in the body distribution and pharmacokinetic properties of the permeability of drugs.2-3 double - bond shift inactivation. 2 - COOH can be made into premedication to increase oral absorption.The constitutive effect of quinolone drugs.A ring (pyridine keto acid) is the basic therapeutic effectsof antibacterial action necessary to group. One of the three carboxyl and four ketone group is with its target enzyme binding sites, is A crucial part of the antimicrobial activity.The B ring part can be changed greatly, and can be incorporated into the benzene ring, pyridine ring and pyrimidine ring.The substitution of the N1 position substituents for the antibacterial activity was greater, and if the hydroxyl group was replaced by the hydroxyl group, the activity was better than that of ethyl, fluoroethyl and cyclopropyl.Two substituents were introduced to reduce or disappear the substituents, possibly due to space resistance blocking the binding of receptors.The carboxyl group and the 4-digit ketones are indispensable part of antibacterial activity.Five amino substituted activity increased. Other groups replaced the activity.Six substituent effect on the activity is very important. Active replace order: F > Cl > > CN = CH2 > = h. introduced F than H antibacterial activity of 30 times. Because the F generation and DNA spiral enzyme enhanced affinity 2-17 times. The penetration enhancement 1-70 times of bacterial cell walls.The order of 7 substituents to be substituted for base enhancement is piperazine > dimethylamine > methylamine > hydrogen, which is the best substitute for piperazine.The 8 bits were replaced by F, Cl and -och3, but they were also enhanced by the substitution of F instead of the phototoxicity. If 1, 8 rings, the photochemical isomers produced by the other were also significantly different.。
