5-HT1-receptor agonists are potent, long acting agents that lower arterial pressure and induce bradycardia in cats, dogs, and rats. 8-OH-2-di-n propylaminotetralin (8-OH DPAT) will serve as the reference chemical and will be compared with newly-synthesized apomorphine derivatives in which the 10-OH group is substituted with CH3, CH2OH, H, etc., as well as altering substitution on nitrogen (aporphines). Preliminary studies ahve demonstrated that the 10-CH3, N-CH3 aporphine derivative parallels closely the behavorial and cardiovascular changes-induced by 8-OH DPAT, a selective 5-HT1A receptor agonist. The aporphine compound has no interaction with DA2-receptors and our hypothesis is that alkyl substitutions in the 10-position of apomorphine introduce potent 5-HT1-receptor agonist properties. The experimental procedures will evaluate possible central and peripheral sites for the hypotensive and bradycardic responses induced by these series of compounds, investigate reflex activations of the sympathetic and parasympathetic nervous systems, and determine receptor selectively and specificity using various radioligand binding and bioassay procedures. Direct goals of this research include: (1) determine the role of 5- HT1 -receptors for control of the cardiovascular system, (2) evaluate present hypothesis is that these agents are potent 5-HT- receptor agonists, and both of these series of agents are very potent in blocking cardiovascular responses to bilateral carotid occlusion, inducing bradycardia and hypotension, (3) identifying agonists for serotonin-receptor subtypes; this is certainly needed to help define physiological roles of this receptor, and (4) since we have no selective antagonists for 5-HT1 receptors, an active agent is clearly needed and this research will identify antagonists for 5-HT1 receptor subtypes. This research will combine chemical and biological experimental procedures to advance our understanding of the role of 5-HT1 receptors in cardiovascular pharmacology.
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