Publications : 1998

Booth RB, Brown RL, Bucholtz ED, Choksi NY, Owens CE, Wyrick S.D. Phenylaminotetralins: A new class of histamine H1-type ligands that affect catecholamine synthesis and release in vitro and in vivo. Society for Neuroscience Abstracts, 24:1838, 1998


Phenylaminotetralins (PATs) recognize a binding site (PAT-site) in guinea pig (GP) forebrain that can be stereoselectively labeled with the radioligand [3H]-(-)-ZraA?5-H2- PAT (Kf)=0.13 nM). PAT sites are highly localized in the catecholaminergic nerve terminal regions striatum, hippocampus, and nucleus accumbens (NA). The medicinal chemistry and pharmacology of PAT sites is similar to histamine H| receptors. For example, PATs incorporate the diarylaminopropane pharmacophore present in histamine H, antagonists like triprolidine and (-)-frww-H2-PAT antagonizes histamine-induced accumulation of inositol triphosphate in astrocytoma cells. In GP brain, diarylaminopropane H| antagonists (mepyramine, diphenhydramine, [-1-]- chlorpheniramine, triprolidine) bind with high affinity (K05<5 nM) to PAT sites; (-)- and (i)-/ra/7.y-H2-PAT have high affinity (KO5=1.4, 3.4 nM) for H, receptors; and distribution of PAT and H] sites is similar. In vitro, (±)-/ram-H2-PAT stimulates tyrosine hydroxy lase (TH) activity and dopamine (DA) synthesis (25% at 0.1 pM) in GP and rat striatum; this effect is blocked by triprolidine. (±)-7ram-H2-PAT also stimulates DA release (to 300% control) in rat striatum, but this effect only occurs at high concentrations (>100 pM) and is not antagonized by PAT-site ligands. In vivo, in a rat presynaptic model, low doses (4-40 nmol/kg, ICV) of (±)-/rara-H2-PAT stimulate TH activity and DA synthesis in NA to 200% control and this effect is fully blocked by triprolidine; at higher doses, the stimulation of DA synthesis is attenuated to control. This negative neuromodulatory effect on DA synthesis likely is due to feedback mechanisms resulting from released DA. (±)-7ra/7s-H2-PAT did not significantly affect DA synthesis in striatum in vivo. Ongoing rat brain receptor mapping and binding studies will examine the limbic functional selectivity of (±)- /ra/7.y-H2-PAT and H ¡-like nature of presynaptic PAT-sites.