Antagonistic compounds

The benzodiazepines currently available for clinical use vary substantially in pharmacokinetics, acute euphoriant effects, and frequency of reported dependence. It is likely, therefore, than not all benzodiazepines have the same potential for abuse. Diazepam, lorazepam, and alprazolam may have greater abuse potential than chlordiazepoxide and clorazepate (Wolf et al. 1990). Similarly, oxazepam has been reported to produce low levels of abuse (Eliding 1978). Jaffe et al. (1983) found that in recently detoxified alcoholic patients, halazepam produces minimal euphoria even at a supratherapeutic dosage. The development of partial agonist and mixed agonist/antagonist compounds at the benzodiazepine receptor complex may offer an advantage over approved benzodiazepines for use in alcoholic patients. 

An azetidine motif was also present in two series of CBi antagonist compounds disclosed by Vernalis Research [335, 336]. In the former, compound (560) was claimed to have an affinity of 285 nM in transfected HEK293 cells using tritium-labelled (382). Among the preferred indications were psychosis, schizophrenia, smoking cessation and eating disorders associated with excessive food intake. Compound (561) was claimed to have an affinity of 0.8 nM in the same binding assay [336]. 

Treatment of a methanolic solution of the nitrile derivatives (81 R1 = CH2CN, R2 = CONH2) [prepared in two steps from the calcium antagonist compound (81 R1 = R2 = H)] with sodium hydride resulted in facile cyclization, giving the 4-aminoimidazol-2-one derivative (82) (53%) (90JMC1805). 

Other modifications of the non-constrained PAF framework have led Hoffmann La Roche s group to develop a further series of antagonistic compounds. The two closely related tetramethylene derivatives, both designated Ro 19-3704 (4c), are the most efficient and inhibit PAF-induced rabbit platelet aggregation with an IC50 value of 3.0 and 0.4 /iM respectively [113]. 

A furo[3,4-c]pyridinone ring is incorporated in compound 149, a neuropeptide Y antagonist. Compound 149 is currently under investigation for possible use in the treatment of obesity <2005JOC9222>. 

Figure 2.3 Schematic dose-response curves. Curves a and b (with different values) show the actions of drugs in the same series acting on the same receptor site with different intrinsic activities. Curve c represents a partial agonist of the same series. Thus, a and b are agonists c is a partial agonist. Curve d is the action of a in the presence of a competitive antagonist. Compounds represented by curves a and b have the same efficacy.

The presence of kairomones is usually involved in the selection of a food plant. Resistant plants usually lack or have too little of the normal kairomones, the kairomones are inhibited or blocked by antagonistic compounds or only allomones are present (25,31). 

The results of the receptor binding assay performed using this compound, IA, are shown in Table 4 where it is clear that affinity to the human B2 receptor is improved with respect to compound I. This data is supportive of the notion that the C-terminal residue(s) in this new series of bradykinin antagonist compounds interact with a hydrophobic environment, perhaps within the transmembrane domain of the receptor as previously suggested. 

Dihydropyridines continue to be widely studied and clinically used as calcium channel antagonists. Compounds such as nifedipine 285, felodipine 286, and nicardipine 287 are standard clinically used medicines for the treatment of cardiovascular diseases such as hypertension. 1,4-Dihydropyridines have been discovered to have numerous other biological activities and a review of their diverse use as medicinal compounds was published in 2003 <2003MI2>. 

Recently, Hop et al. [131] used a combination of LC/MS, LC/MS/MS, and NMR techniques to identify metabolites of a substance P (Neurokinin 1 receptor) antagonist, compound A (Scheme 10), in rat hepatocytes and rat plasma. In both in vitro and in vivo studies, the samples were prepared for analysis by... 

Cannabis is known to stimulate appetite, and promote food intake ( the munchies ). The identification of cannabinoid (CB1) receptors in the brain allowed the development of selective antagonist compounds such as Ri-monabant, which was found to suppresses food intake in laboratory animals (Colombo et al. 1998). Clinical trials have shown it to be significantly more effective than placebo in assisting overweight patients lose weight (see Chapter 8). 

A series of dihydropyrrolo[2,3-d] pyrimidines was prepared as potent corticotropin-releasing factor-1 receptor antagonists. Compound 37 exhibits moderate oral bioavail-abihty (F = 21%) and a brain-to-plasma (B/P) ratio of 0.6. Compound 38, on the other hand, has high oral bioavailability (F = 86%) and a B/P ratio of 2.3. The increases in bioavailability and B/P ratio are attributed to the 4-fold decrease in clearance exhibited by 38, compared to 37. In general, dialkylamine or cychc aliphatic amine substituted pyrimidines had higher plasma clearance and volumes of distribution than compounds bearing aromatic substituents, which, in turn, resulted in compounds having better oral bioavailability and B/P ratios. 

A series of carbazole analogs was prepared as neuropeptide Y (NPY) antagonists. Compound 47 was found to have a high affinity for NPY, but had poor permeability properties in vivo with a B/P ratio of 0.1. The pKr for 47 was calculated to be 11.0 and thought to be a major cause for the poor PK profile. Efforts to decrease the led to 48, which had a pK = 9.7 and a better B/P ratio of 0.8. Finally, by decreasing the pK even further to 7.9, compound 49 gave very good brain penetration and had a B/P ratio of 4.2. 

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