P-Antagonist

The use of selective P-antagonists for treatment of CHF has included the P -blocker metoprolol (Table 1) and results of clinical trials suggest long-term beneficial effects. Selective P -antagonists have also been tested, an example of which is xamoterol [81801 -12-9], C2 H25N20, which is (i)-A/-(2-hydroxy-3-(4-hydroxyphenoxy)propylamino)ethylmorphine-4-carboxamide. Xamoterol exhibits approximately 50% of the activity of isoproterenol, and serves to provide modest inotropic effects (128,129). 

The reacdon of y-nitrobiitenoate v/ith aldehydes and ketones in the presence of ammonium acetate gives 3-nitropiperidines. This reacdon is used for synthesis of CP-99,994, a highly potent substance P antagonist fScherae 10.23. ... 

The 2(lH)-pyrazinone system has received increased interest in the past two decades by both synthetic and biological research, due to its presence in a variety of natural and non-natural products as well as pharmacologically active compounds. The easy and diverse methods for the generation of this versatile scaffold make it a prime choice for the current pharmaceutical research hke thrombin inhibitors, substance P antagonists, etc. The rich 1,4-azadiene... 

Controversy surrounds the selection of a P-blocker for HF management. First, although metoprolol and carvedilol are the most commonly used p-antagonists in HF, it remains controversial as to whether one agent should be considered first-line. Carvedilol exhibits several pharmacologic properties that theoretically would confer superior efficacy, since carvedilol (1) provides blockade at multiple adrenergic receptors, which... 

The answer is F. (Katzung, p 167, Hardman, pp 237-2382 Labetalol has potent a and p antagonist actions, due to the specific components of its racemic mixture of four isomeric compounds. Cardiac output and heart rate change minimally, while blood pressure decreases due to a overall reduction in peripheral resistance. The combined a and p antagonism has been found to be of advantage in treating pheochromocytomas. 

One final mechanism that has recently shown promise for antidepressant effects appears distinct from all of the monoamine systems. A study published in 1998 demonstrated that a substance P antagonist (MK-869) had antidepressant effects in humans (Kramer et al. 1998). Substance P is localized to many areas of the brain that are involved in emotional processing, including the amygdala, dentate gyrus, subiculum, nucleus accumbens, striatum, locus coeruleus and periaqueductal grey (Kramer... 

Kamel AM, Zandi KS, Massefski WW. 2003. Identification of the degradation product of ezlopitant, a non-peptidic substance P antagonist receptor, by hydrogen deuterium exchange, electrospray ionization tandem mass spectrometry (ESI/MS/MM) and nuclear magnetic resonance (NMR) spectroscopy. J Pharm Biomed Anal 31 1211. 

Folkers K, Hakanson R, Horig J, Xu JC, Leander S (1984) Biological evaluation of substance P antagonists. Br J Pharmacol 83 449-456... 

A. Both sets of responses to isoproterenol are mediated by p-adrenoceptors, and all the choices are p-antagonists. However, drug X is more effective in antagonizing cardiac responses to isoproterenol than it is the bronchiolar responses. Drug X is therefore a cardioselective p-blocker, that is, selective for Pi over P2 receptors. Metoprolol is the only pi-selective antagonist among the choices. 

The intramolecular Diels-Alder reaction of l-(A -a -alkenyl)-2(l//)-pyrazinones generates m-[l,7]naphthyridines in good yields (Scheme 62) <2001TL7397>. This method has been used in the development of a r-[l,7]naphthyr-idine-based scaffold on which to build a type VI external /3-turn mimic <2003EJ01868>, and for the synthesis and conformational analysis of [l,7]naphthyridine-based substance P antagonist analogues <2003T4721>. 

---