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Bottom: 4-substituted histamine derivatives act as proton-transfer agents in their tele-tautomeric form cheapest bimat symptoms of the flu. H1 receptors are not very specific and are occupied by antidepressants and neuroleptics as well order generic bimat from india symptoms of colon cancer. The H1 receptors are easily solubilized and have been purified on lectin affinity columns generic 3 ml bimat visa medications used to treat anxiety, indicating their glycoprotein nature buy discount bimat 3 ml online medicine 524. H2 receptors are localized to the cortex and striatum and are found in neurons, glial cells (astrocytes), and blood vessels. Thus the role of the central histamine receptor may not be information transmission, but sensitization of brain areas to excitatory signals from “waking amines. H3 receptors have been described and seem to be localized in cortex and substantia nigra; these seem to be presynaptic autoreceptors, controlling histamine release and synthesis. They are activated by histamine concentrations that are two orders of magnitude lower than those necessary for triggering postsynaptic receptors. Their blockade may potentially lead to increased blood flow and metabolism combined with a central arousal, whereas their stimulation (or inhibition of central H2 receptors) could have a sedative effect. Histamine-mediated hypothermia, emesis, and hypertension have been shown to exist, and the well-known sedative effects of H1 antihistamines are centrally mediated. Large alkyl groups on C-4 decrease activity and lead to partial agonists, whereas side-chain N-substitution enhances the antagonistic properties of the molecule. It is a selective H2 agonist, having between 19% and 70% H2 activity, with no effect on the H1 receptor. The circulatory effects are manifested as arteriolar dilation and increased capillary permeability, causing plasma loss. The localized redness, edema (hives, wheal), and diffuse redness seen in allergic urticaria (rash) or physical skin injury result from these circulatory changes. Humans and guinea pigs are very prone to bronchoconstriction by histamine (an H1 effect), and severe asthmatic attacks can be triggered by small doses, provided the person suffers from asthma and is therefore very sensitive to histamine. Stimulation of gastric acid secretion is the most important H2 response; it is blocked only by H2 antagonists. As mentioned before, the hormone gastrin may be involved in histamine release, because H2 antagonists block gastrin-induced acid secretion. H3 receptors are involved in mediating the neuroregulatory influence of the brain on stomach, lung, and heart. Replacement of the amino group with bioisosteric polar cationic groups yields imetit (4. They do not bear any close resemblance to the agonist since their binding involves accessory binding sites. Ethylenediamines, aminoalkyl ethers, and aminopropyl compounds, for which X is nitrogen, oxygen, and carbon, respectively, show a general H1 antagonist structure. The theophylline derivative was originally added to counteract the drowsiness produced by diphenhydramine, since it is a central excitant related to caffeine. They are quite polar molecules and therefore cannot cross the blood–brain barrier to reach central histamine receptors. One of the compounds that showed weak H2-antagonist activity, guanyl- histamine, was the point of departure in the development of these drugs. Extension of the side chain was found to increase the H2-antagonist activity, but some agonist effects were retained. When the very basic guanidino group was replaced by the neutral thiourea, burimamide (4. Introduction of the electron-withdrawing sulfur atom into the side chain reduced the ring pKa. The proportion of the cationic form was also decreased, and the tele tautomer became predominant. Reduced ionization improved the membrane per- meability of the molecule; the oral absorption of the resulting compound, metiamide (4. However, metiamide still showed some side effects in the form of hema- tological and kidney damage, which were attributed to the thiourea group. A satisfactory replacement was found by substituting another electron-withdrawing group on guanidine while retaining the appropriate pKa. It then became clear that an imidazole nucleus was not absolutely necessary for H2-antagonist activity. Treatment of peptic ulcers is a complicated and multilevel therapy in which H2 antagonists are very successful and widely used (and abused). Peptic ulcers may affect either the stomach (gastric ulcers, less common overall but more common in people with iatrogenic [i. This mucosal damage is promoted by Helicobacter pylori bacteria that colonize the gastric lining. To facilitate healing, prevent ulcer recurrence, and relieve pain, the medicinal chemistry approach is multipronged and involves lowering aggressive acid output, augmenting the mucous-based protection, and/or eradicating the Helicobacter pylori. The concentration of acid in the stomach may be reduced either by neutralizing the acid or by inhibiting acid production. The next major class of drugs for peptic ulcer disease is the mucoprotectants and other protective agents. Finally, since the microorganism Helicobacter pylori plays an important role in the pathogenesis of ulcers, antibacterial agents such as amoxicillin (4. The nonsurgical treatment of peptic ulcer is a superb example of how multiple mole- cular approaches can be used to therapeutically attack a single clinical problem from multiple directions. Also, the medical management of peptic ulcer disease demonstrates how antagonists of neurotransmitter messenger molecules (acetylcholine, histamine) can be used to treat nonneurological disorders. The role of β-adrenergic agonists and antag- onists in the treatment of cardiopulmonary diseases is a similar example. Thioperamide, a prototypic H3 antagonist, enhances arousal patterns in cats, an observation which has been confirmed using other nonthiourea H3 blockers. They are very effective at reducing the “runny nose and itchy eyes” (allergic rhinitis and allergic conjunctivitis) of allergies. However, since they are effective at reducing the runny nose of allergies, antihistamines are frequently used in “cold remedies. Regrettably, the antihista- mines are usually listed as one of several active agents within a “shotgun” cold remedy. Since H1 receptors are diffusely located throughout the brain, cold remedies can cause drowsiness (a danger to those operating moving equipment) and may, rarely, even trigger seizures in a person with a predisposition to epileptic seizures. The same molecules used to treat allergies and “cold symptoms” have many other uses. Antihistamines are particularly effective as antiemetics in suppressing nausea associated with gastrointestinal illnesses. They can also be used to treat the symptoms of motion sickness or even vestibular disturbances (vertigo). Because of their ability to induce sedation, antihistamines are widely used in over-the-counter sleep aids. The amounts present are relatively high—on a µmol/g order of magnitude—rather than the nanomolar quantities seen with most major neurotransmitters. The great increase in research activity in this area was largely due to the recognition that the extremely widely used benzodiazepine tranquilizers (e.
It is the drug of choice for Clostridium-difficile-associated pseudomembranous colitis discount bimat online american express medicine 7253 pill. It is also used in penicillin-allergic pregnant women for bacterial endocarditis prophylaxis order bimat 3 ml on line medications held before dialysis. There is no available scientific information linking this agent with adverse pregnancy outcomes buy bimat from india medications available in mexico, including congenital malformations generic bimat 3 ml fast delivery medications given for uti. However, vancomycin may be associ- ated with significant maternal side effects, such as nephrotoxicity and ototoxicity. Although there are no such reports, vancomycin could theoretically result in the same toxicity in the fetus, since this drug readily crosses the placenta. Aztreonam Aztreonam belongs to a relatively new class of antibiotics: the monobactams. It is effec- tive against most of the aerobic Gram-negative rods or Enterobacteriaceae, and is used as an alternative to the aminoglycosides. However, according to its manufacturer, aztreonam has not been shown to be teratogenic in several animal models given several times the human dose. Moreover, a particular advantage of this antibiotic over the aminoglycosides is that it is not associated with either nephrotoxicity or ototoxicity in either the mother or the fetus. It is presently combined with cilastatin, which inhibits the renal metabolism of imipenem. Imipenem is effective against a wide variety of 34 Antimicrobials during pregnancy Gram-positive and Gram-negative aerobic and anaerobic organisms. It has the potential to be very effective as single-agent therapy for polymicrobial pelvic infections in women. There are no available human reproductive studies, but the imipenem–cilastatin combi- nation has not been shown to be teratogenic in rats or rabbits, according to its manu- facturer. There are few indications for the use of this very ‘potent’ antibiotic in pregnant women. Potential maternal side effects include hypersensitivity, central nervous system toxicity, and pseudomembranous colitis. Quinolones Ciprofloxacin, norfloxacin, and ofloxacin belong to the fluoroquinolone group of antibi- otics. They are very effective against the aerobic Gram-negative bacilli, and hence are espe- cially useful for the treatment of urinary tract infections. They also exhibit good activity against a variety of aerobic Gram-positive organisms, although most anaerobes are resistant to both antibiotics. Among 549 pregnancies that were exposed to quinolones during the first trimester, there were the following exposures: 318 norfloxacin, 93 oflaxacin, 70 ciprofloxacin, and 57 pefloxacin (Schaefer et al. Analyses controlled for various confounding factors, and it was found that the frequency of congenital anomalies was not increased above back- ground (3. However, two of the defects associated with ofloxacin exposure were secondary to prematurity (undescended testicle and inguinal hernia). When these two infants were excluded from the analysis, the frequency of congenital anomalies was not increased above background. Norfloxacin was not found to be teratogenic when given to monkeys during the critical period of organogenesis (Cukierski et al. However, according to the manufac- turer, quinolones may cause lameness or irreversible arthropathy in immature dogs Box 2. It should be noted that approximately 2 percent of women taking these drugs experienced a reversible skin rash and photosensitivity (Christian, 1996). Naldixic acid, another quinolone, was associated with pyloric stenosis but the rela- tionship is apparently not causal. Although data are not adequate to exclude a risk of birth defects following exposure during the first trimester, it seems unlikely that naldixic acid poses a substantial risk of birth defects (Friedman and Polifka, 2006). Other quinolones have not been investigated for use during pregnancy: moxifloxacin (Avalox), gatifloxacin (Tequin), levofloxacin (Levaquin), garebixacin, and gemifloxacin. Azithromycin No epidemiological studies of azithromycin use during pregnancy have been published. Although, it does not seem to be associated with a high risk of congenital anomalies follow- ing first-trimester exposure, a small risk cannot be excluded (Friedman and Polifka, 2006). In a review of 15 studies involving 446 pregnancies exposed to rifampin, Snider and coworkers (1980) reported a malformation rate of 3–4 percent, similar to that of the general population. There were also over 600 pregnancies exposed to ethanbutol and almost 1500 exposed to isoniazid without evidence of an increase in congenital malfor- mations (Snider et al. This most potent teratogen should obviously be avoided in pregnant women or those likely to become pregnant. Nystatin, clotrimazole, and miconazole These agents are utilized primarily for the treatment of candidiasis. In at least two recent reports there were no increases in malformations from their use (Jick et al. Butoconazole, terconazole, and ketoconazole There are no large studies of the use of these three antifungal agents during pregnancy. Butoconazole is a category B drug, and the other two are listed as category C by their 36 Antimicrobials during pregnancy Box 2. It seems unlikely that these agents would have significant, if any, terato- genic risks. Fluconazole Fluconazole is an azole antifungal similar to ketoconazole and is utilized for both local and systemic fungal infections (Hollier and Cox, 1995). It is useful in the treatment of vaginal, oral, and systemic candidiasis, as well as for prophylaxis and treatment of cryp- tococcal infections in immunocompromised patients (i. Among 239 women who took single low doses of fluconazole, 60 took it during the first trimester of pregnancy. Antifungals 37 However, four cases of craniosynostosis with radial-humeral bowing and tetrology of Fallot have occurred following repeated high-dose fluconazole for cocci meningitis (Aleck and Bartley, 1996; Lee et al. In one study of 226 pregnancies exposed to fluconazole during the first trimester, the frequency of congenital anomalies was not increased (Mastroiacovo et al. Maternal side effects may include headache, dizziness, or gastroin- testinal upset. Ciclopirox This is a relatively new, topical antifungal agent effective against various dermatophytes such as Trichophyton species and Candida albicans. There is little, if any, information regarding its use during pregnancy but, according to its manufacturer, it was not terato- genic in various animal studies. Tolnaftate, undecylenic, and terbinafine Both tolnaftate (Tinactin) and undecylenic acid (Desenex) are utilized for dermatophyte infections such as tinea pedis and tinea corporis, but are not effective against yeast (Davis, 1995). There are no reports of these agents being teratogenic, and it would seem reasonable to classify them as category B agents at the present time.
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In this case cheap bimat american express treatment lice, the rise of the affected drug to its new plateau virtually mirrors in time the approach of the inhibitor to its plateau buy 3ml bimat with amex medications 4h2. Also shown in Figure 13 is the return of the affected drug to its previous plateau on withdrawing the offending drug purchase bimat discount medicine 6 clinic. This return is faster than during the rise in the presence of the inhibitor purchase bimat pills in toronto medicine research, because as the inhibitor falls, so does the degree of inhibition, which then causes a shortening in the half-life and thus an ever-accelerating decline of the affected drug. However, the speed of decline is strongly determined by the kinetics of the inhibitor. If it has a long half-life, its decline may be the rate-limiting step in the entire process, in which case the decline of the inhibited drug parallels that of the inhibitor itself. But there are many pharmacokinetic interactions other than those occurring at enzymatic sites, such as those involving transporters or altered physiological function. Transporters The quantitative and kinetic conclusions reached with metabolic drug inter- actions apply equally well to those involving transporters effecting excretion, which reside in organs connected with the exterior, such as the liver via the bile duct (see Chaps. Sometimes, a transporter interaction occurs within internal organs, such as the brain, to produce altered drug distribution, not excretion. Even so, because the brain comprises less than 1% of total body weight, changes in the distribution of a drug within it, even when quite profound and of major therapeutic conse- quence, will have minimal effect on the volume of distribution of the drug, V, which reflects its overall distribution within the body. Absorption Many interactions involve a change in either the rate or the extent of drug absorption, particularly following oral administration. There are many potential sites for interaction: within the gastric and intestinal lumen, at or within the gut wall, as well as within the liver (Figure 14). As indicated in Figure 15, the consequences of a change in absorption kinetics depend on whether the affected 22 Rowland Figure 14 Schematic depiction of events occurring during absorption after oral administration of a drug. On dissolution, the drug, in addition to having to permeate the intestinal wall, must pass through the liver to reach the systemic circulation and subse- quent sites within the body. Loss of the drug can occur at any of these sites, leading to a loss of oral bioavailability. Although clear dif- ferences are seen after a single dose (left panel), these will also be seen at plateau only if the drug is dosed relatively infrequently (once every 24 hours in this scenario), when little accumulation occurs (middle panel). With frequent dosing (once every 6 hours), accu- mulation is extensive, so changes in absorption kinetics now have only a minor effect at plateau (right panel). Introducing Pharmacokinetic and Pharmacodynamic Concepts 23 drug is given once or as a multiple-dosing regimen. A slowing in absorption kinetics will always result in a lower and later peak concentration, which could be critical if the affected drug is intended for rapid onset of action, such as for the relief of a headache. However, whether this difference is sustained on multiple dosing depends heavily on the dosing frequency of the affected drug relative to its half-life. When it is given infrequently, there is little accumulation, so the events at plateau are similar to those seen following a single dose. However, when given relatively frequently, because of extensive accumulation the amount absorbed from any one dose is such a small fraction of that in the body at plateau that events at plateau are insensitive to changes in absorption kinetics. In con- trast, changes in the extent of absorption seen during single-dose administration, whatever the cause, will still be seen on multiple dosing, irrespective of the frequency of drug administration. Also, while measurement of F is important, which in turn requires the administration of an intravenous dose, it is almost impossible to rationally interpret a drug interaction affecting oral bioavailability without some estimate of the events occurring at at least one of the three sites of loss. It usually requires additional studies to be undertaken to untangle the various events, such as comparing the interaction with both a solution and the usual solid dosage form of the affected drug. Clearly, if no difference is seen, it provides strong evidence that the interaction is not the one affecting the dissolution of the drug from the solid. Furthermore, the lack of an interaction following intravenous dosing of the affected drug would then strongly point to the interaction occurring within the intestinal wall. Displacement With many drugs highly bound to plasma and tissue proteins, and with activity residing in the unbound drug, there has been much concern that displacement of drug from its binding sites could have severe therapeutic consequences. Indeed, had no plasma measurements been made, one would have been totally unaware that an interaction had occurred. Furthermore, if plasma measurements are made, it is important to determine the fraction of the unbound drug and its free concentration; otherwise, there is clearly a danger of misinter- pretation of the interaction. Most are either beyond the scope of this introductory chapter or are covered elsewhere in this book. One is that sometimes drug interactions are multidimensional, with more than one process affected. For example, although no longer prescribed, the anti- inflammatory compound phenylbutazone interacts with many drugs, as is well documented. One in particular is noteworthy here, namely, the interaction with warfarin causing an augmentation of its anticoagulant effect. On investigation, it was found that phenylbutazone not only markedly inhibits many of the metabolic pathways responsible for warfarin elimination, but also displaces warfarin from its major binding protein, albumin, making interpretation of the pharmacokinetic events based on total plasma concentration problematic (13,14). In such sit- uations, and indeed whenever possible, interpretation should be based on the more relevant unbound drug. For example, increasing evidence points to the small intestine, in addition to the liver, having sufficient metabolic activity to cause appreciable loss in the oral bioavailability of some drugs. Then unambiguous quantitation of the degree of involvement of each organ in an interaction in vivo becomes difficult, unless one has a way of separating them physically, such as by sampling the hepatic portal vein, which drains the intestine, to assess the amount passing across the intestinal wall, as well as the systemic circulation to assess the loss of the drug on passage through the liver. Still another is the metabolites themselves, which may possess pharma- cological and toxicological activity in their own right. Each metabolite has its Introducing Pharmacokinetic and Pharmacodynamic Concepts 25 own kinetic profile, which is often altered during an interaction, through a change either in its formation or occasionally in its elimination and distribution. Despite these complexities, however, measurement of both a drug and its metabolites can often be very informative and provide more definitive insights into an interaction than gained from measurement of the drug alone (5). The last complexity mentioned here is the pharmacokinetics of the inter- acting drug itself, be it an inhibitor, an inducer, or a displacer. Given that drug interactions are graded and recognizing that individuals vary widely in their degree of interaction for a given dosage regimen of each drug, it would seem sensible to measure both of them when characterizing an interaction. Even in vitro, all too often it is assumed that the concentration of the interactant is that added, without any regard to the possi- bility that it may bind extensively to components in the system or be metabol- ically degraded. In both cases, the unbound compound of the interacting drug is lower than assumed and if ignored may give a false sense of comfort, suggesting that higher (unbound) concentrations are needed to produce a given degree of interaction than is actually the case. When measured in vivo, it is usually the interacting drug in the circulating plasma rather than at the site of the interaction, such as the hepatocyte, that is inaccessible. In addition, the liver receives the drug primarily from the portal blood, where the concentration may be much higher than in plasma during the absorption phase of the interactant, making any attempt to generate a meaningful concentration-response relationship difficult. Finally, because many drug interactions involve competitive processes, the possibility always exists that the interaction is mutual, with both drugs affecting each other, the degree of effect exerted by each on the other depending on the relative concentrations of the two compounds. Through careful planning and subsequent analysis of both in vitro and in vivo data, progress is being made in our understanding of the mechanisms and pharmacokinetic aspects of drug interactions. In the former case, the change in response is caused by a change in the concentration of the affected drug, together perhaps with one or more metabolites. One feature commonly experienced in pharmacodynamics but much less in pharmacokinetics is saturability, giving rise to nonlinearity. The increase in toxicity for a drug with a wide therapeutic window is minimal (left panel).
Perhaps not surprisingly purchase 3 ml bimat amex treatment nurse, it is initially an agonist that causes a depolarisation of muscle fibres and actual twitching purchase bimat 3ml on-line treatment for strep throat, before producing a depolarisation block of transmission purchase discount bimat on-line medications known to cause hair loss. There are a large number of competitive antagonists apart from curare cheap 3 ml bimat with amex symptoms viral infection, such as gallamine, pancuronium and atracurium, while decamethonium works like suxamethonium as a depolarising agent. Drugs that block the nicotinic receptors on autonomic ganglia, such as hexamethonium, probably do so by actually blockingthe Na ion channel rather than the receptor. In contrast to the nicotinic antagonists and indeed both nicotinic and muscarinic agonists, there are a number of muscarinic antagonists, like atropine, hyoscine (scopolamine) and benztropine, that readily cross the blood±brain barrier to produce central effects. Somewhat surprisingly, atropine is a central stimulant while hyoscine is sedative, as least in reasonable doses. Generally these compounds are effective in the control of motion but not other forms of sickness (especially hyoscine), tend to impair memory (Chapter 18) and reduce some of the symptoms of Parkinsonism (Chapter 15). Much effort has been expended in the search for more specific muscarinic agonists and antagonists and while a few compounds have emerged which, from binding studies at least, show some (but never dramatic) selectivity, the results have been somewhat disappointing. Even then the peripheral effects of the M2 antagonist such as dry mouth and blurred vision can be unpleasant. Such possible permutations of agonist and antagonists in the treatment of dementia are considered in more detail in Chapter 18. In the striatum it is released from intrinsic interneurons and in the cortex from the terminals of ascendingaxons from subcortical neurons in defined nuclei. Such collaterals innervate (drive) an interneuron (the Renshaw cell) in the ventral horn of the spinal cord, which provides an inhibitory feedback onto the motoneuron. Also the activation of Renshaw cells, by such stimulation, is not only potentiated by anticholinesterases but is also blocked by appropriate antagonists. Stimulation produces an initial rapid and brief excitation (burst of impulses), which is blocked by the nicotinic antagonist dihydro-b-erythroidine, followed, after a pause, by a more prolonged low-frequency discharge that is blocked by muscarinic antagonists and mimicked by muscarinic agonists. This nucleus, together with the diagonal band, forms the sub- stantia innominata and the dorsal neurons of this band also join with those in the medial septum to provide a distinct cholinergic input to the hippocampus (Fig. Certainly antimuscarinic drugs like atropine are well known to impair cognitive function in both animals and humans. In the former antimuscarinic drugs appear to impair both the acquisition and retention of some learned tasks, as in the Morris water maze. This involves placinga rat in a circular tank of water containinga stand with a platform just below the surface but which is not clearly visible because the vessel walls or water have been made opaque. Generally the rat quickly learns (2±3 trials) to identify the position of and swims to the platform. Since these appear to synchronise the activity of the main hippocampal glutamate neurons their stimulation could influence hippocampal function and memory process (see Jones, Sudweeks and Yakel 1999). Flentge, F, Venema, K, Koch, T and Korf, J (1997) An enzyme-reactor for electrochemical monitoringof choline and acetylcholine. Applications in high-performance liquid chromato- graphy, brain tissue, microdialysis and cerebral fluid. Zinnerman, H, Volknandt, W, Wittich, B and Hausinger, A (1993) Synaptic vesicle lifecycle and synaptic turnover. A8 is lateral, caudal and somewhat dorsal to A9 and A10 whereas A10 is ventral to A9. There is in fact no clear divide between A9 and A10 and some overlap of their pathways. While the nigrostriatal pathways are ipsilateral some crossing occurs in fibres from the ventral tegmental A10 nucleus. Further details can be obtained from Moore and Bloom (1978) and Lindvall and Bjorkland (1978). It is concentrated in the striatum (10 mg/g), nucleus accumbens (5 mg/g) and olfactory tubercle (6 mg/g) but in the cortex there is much less (0. Cells in the substantia nigra in humans and primates differ from those in other species in containing granules of the lipoprotein pigment called neuromelanin. Cells in this nucleus can also have hyaline inclusion bodies, the Lewy bodies, which are not common normally but appear to increase dramatically in patients with Parkinsonism. Certainly they will require considerable biochemical back-up to maintain function in all their terminals. It appears to be transported into the brain after synthesis from phenylalanine (phenylalanine hydroxylase) in the liver rather than from phenylalanine found in the brain. This enzyme, which requires pyridoxal phosphate (vitamin B6) as co-factor, can decarboxylate other amino acids (e. Until recently the only inhibitors of this enzyme were pyragallol and catechol which were too toxic for clinical use. This transporter has been shown to be a 619 amino-acid protein with 12 hydrophobic membrane spanning domains (see Giros and Caron 1993). This can be disrupted by the rauwolfia alkaloid, reserpine and by drugs like tetrabenazine. Although most of these receptors appear to be of the D2 type, as found postsynaptically, D3 receptors are also found. It is possible that in addition to the short-term control of transmitter release they may also be linked directly to the control of the synthesising enzyme tyrosine hydroxylase. It seems that autoreceptors are more common on the terminals of nerves in the nigrostriatal (and possibly mesolimbic) than mesocortical pathway. The release and changes in it may also be slower and longer than that at axon terminals and the synaptic arrangement between the releasing dendrites and postsynaptic target is not clear. To produce a central effect it must be administered directly into the brain by intracerebroventricular (icv) injection. Ligand-binding studies, originally with [3H] dopamine and [3H] haloperidol but subsequently using [3H] spiperone, demonstrated the existence of a specific binding site for them in membrane preparations from mammalian striatum. Displacement studies with a whole range of neuroleptic drugs also showed that not only was the rank order different from that for blocking the adenylate cyclase but also correlated much better with antipsychotic activity. One was linked to stimulation of adenylate cyclase (D1) while the other (D2) did not appear to be associated with the enzyme but had distinct binding sites. Although some subsequent pharmacological studies suggested that perhaps there could be a subdivision of both the D1 and D2 receptors, the paucity of appropriate agonists and antagonists (and indeed of test responses) precluded its justification until molecular biology took over. The D1 and D5 receptors are linked to activation of adenylate cyclase and the D2 group to its inhibition, although this is not its main effect on neurons (see later). Although the above nomenclature is now accepted it might have been better, as suggested by Sibley and Monsma (1992), to retain D1 and D2 to represent the two families and then subdivide them as D1A for (D1), D1B for (D5), then D2A for (D2), D2B for (D3)andD2C for (D4), even though variants of all five have been found. Blocked by neuroleptics Ð similar in effectiveness to their binding affinities (b). Notes: Studies with various agonists and antagonists showed that the effects on (a) differed in potency from both (b) and (c) and were thus associated with a receptor (D1) different from that (D2) linked to (b) and (c). The human D2 receptor shows a protein sequence which is 96% identical to that of the rat D2 and although the similarity is only 91% between the human and rat D1 receptor, it is 96% in the transmembrane region. It is differences in the amino-acid sequences in this region that primarily justify the classification into two groups (D1 and D2) rather than their total amino-acid number.