Acknowledgements

We thank Sukhwinder Thandi for assistance with the Figures and her helpful comments on earlier drafts of the manuscript. Cited and ongoing studies from the authors' own laboratories are supported by the Wellcome Trust and the Medical Research Council. Aiba A, Kano M, Chen C, Stanton ME, Fox GD, Herrup K etal. (1994). Deficient cerebellar long-term depression and impaired motor learning in mGluRl mutant mice. Cell 79, 377-88. Alblas J, van Corven EJ, Hordijk PL, Milligan G, and Moolenaar WH...

Functional diversity of Ga subunits

The classification of G proteins is based on their amino acid identities and functional specialization of their Ga subunits (Simon et al. 1991). There are four major subfamilies of Ga subunits and their general properties are listed in Tables 4.1 and 4.4. The largest subfamily is generally known as 'inhibitory' Ga subunits, after the identification of the negative regulator of AC, Ga . All members except Gaz are subject to ADP-ribosylation mediated by the bacterial toxin from Bordetella...

Cellular and subcellular localization

Both galanin receptors show a widespread anatomical distribution throughout the central and peripheral nervous systems (Fig. 16.2). In 1986, both Melander et al. and Skofitsch et al. used receptor autoradiography to determine the distribution of 125I -galanin binding sites in the rat CNS (Fig. 16.2) (Melander etal. 1986a Skofitsch etal. 1986). Dense galanin binding was observed in the prefrontal cortex, the anterior nuclei of the olfactory bulb, several nuclei of the amygdaloid complex, the...

Peripheral indications

Knockout and overexpression experiments have been reported only for the a1b-adrenoceptor subtype. Knockout of the a1b-adrenoceptor results in impaired vascular responsiveness to phenylephrine, demonstrated both in isolated blood vessels and through measurement of blood pressure responses in anesthetized mice (Cavalli et al. 1997). Cardiac specific overexpression of the a1b-adrenoceptor results in an impairment of cardiac function without cardiomyocyte hypertrophy (Grupp et al. 1998). Increased...

Affinity measurements in functional studies

As with binding, antagonists produce distinctive effects on dose-response curves for agonists. In all cases but non-competitive and pseudo-irrevesible antagonism, the effects are the same as those observed on tracer saturation binding curves. Thus, a competitive antagonist produces parallel dextral displacement of dose-response curves with no diminution of maximal response (see Fig. 8.2a). In this case, the affinity of the antagonist can be estimated by Schild analysis, whereby the dose-ratio...

Characterizing orphan receptors using a reverse pharmacology approach

Although complex and technically challenging, the strategy that has become standard for the identification of ligands for orphan GPCRs is known as the 'reverse pharmacology' approach, which is to clearly distinguish it from the more classical approach to drug discovery (Stadel et al. 1997). Historically, the classical approach was initiated by the discovery of a biological or physiological activity that could be attributed to a specific ligand, this was then used to pharmacologically...

Arousal attention and sleep

Centrally acting a1-adrenoceptor agonists often potentiate motor stimulation or arousal produced by other pharmacological (Holz et al. 1982) or behavioural (Astrachan et al. 1983a,b) challenges, and will increase vigilance when administered alone (Nozulak et al. 1992). a1-Adrenoceptor agonists can reverse sedation induced by norepinephrine depletion produced by a dopamine -hydroxylase inhibitor (Nozulak et al. 1992). Likewise, they can reverse cataplexy in a genetic canine model of narcolepsy...

Alzheimers disease and cognition

Extensive literature suggests that the brain histaminergic system can modulate learning and reinforcement. However, many details are lacking, and some findings seem contradictory. For example, several workers have found that microinjections of HA into certain brain areas facilitate cognitive performance and task recall, and pharmacological depletion of brain HA has the opposite effect (Kamei et al. 1993 Leurs et al. 1998). Furthermore, both H1 receptor agonists, and an inhibitor of brain HA...

Interactions between G proteins and GPCRs

G proteins bind to their corresponding GPCRs at multiple sites on the cytoplasmic regions of the receptor. Several regions of Ga contribute toward association with GPCRs, which have been extensively reviewed (Gudermann etal. 1997 Bourne 1997 Hamm 1998). One of the major domains for receptor recognition is the C-terminus of Ga, where PTX-mediated ADP-ribosylation of Gi subfamily members occurs and the receptor-G protein interaction is then disrupted. Replacement of the last five amino acids of...

Anxiety

The initial suggestion that the CCK system might be involved in anxiety came from experiments of Bradwejn and de Montigny (1984) showing that benzodiazepine receptor agonists could attenuate CCK induced excitation of rat hippocampal neurones. Subsequent clinical studies demonstrated that bolus injections of the CCK2 receptor agonist CCK4 or pentagastrin provoke panic attacks in patients with panic disorders (Bradwejn et al. 1991, 1992). Recent investigations have revealed that the panicogenic...

References

Andres ME, Burger C, Peral-Rubio MJ, Battaglioli E, Anderson ME, Grimes J etal. (1999). CoREST A functional corepressor required for regulation of neural-specific gene expression. Proc Natl Acad Sci USA 96, 9873-8. Archer TK, Lefebvre P, Wolford RG, and Hager GL (1992). Transcription factor loading on the MMTV promoter a bimodal mechanism for promoter activation published erratum appears in Science 1992 Apr 10 256(5054) 161 . Science 255, 1573-6. ArranzB, Rosel P, Ramirez N, and San L (2001)....

Epilepsy

The discovery of galanin's effects on epilepsy, where it acts as an anticonvulsant, is a good example of the pre-synaptic inhibitory effects of galanin on glutamate but not on GABA release Ben-Ari 1990 , and shows how it acts as a postsynaptic hyperpolarizing substance to reduce run-away discharges alike Mazarati et al. 1992, 1998, 2000, 2001 . The galanin agonist, galnon, suppresses phenyltetrazole-induced 40 mg kg seizures when injected i.p. 2 mg kg Saar, 2002 . Additional information on the...

Synthesis Of Zolantidine

Synthesis Zolantidine

Drugs which act at the H1 receptor have been known for many years. Discovery of the first HA antagonist over fifty years ago led to an increased understanding of anaphylaxis and allergy, set the stage for demonstrating the likely existence of more than one type of HA receptor, and indirectly led to the subsequent development of phenothiazines and tricyclic antidepressants Green 1983 . Hundreds of the so-called 'classical' or first-generation H1-antagonists have been developed and many are still...