This proposal presents for synthesis and pharmacological evaluation: (1) a series of lysergic acid amides wherein the amide substituent is derived from a chiral amine, (2) a tricyclic ergoline analogue where the pyrrole ring of the ergoline has been replaced with a dihydrofuran ring and, (3) a benz[cd]indole with a pyrrolidine ring cis-fused across the 4-amino-C(3) positions. The latter two series will be resolved into their enantiomers. All compounds will be tested for substitution in the two-lever drug discrimination paradigm, in rats trained to discriminate saline from ip injections of LSD tartrate (0.08 mg/kg). Compounds will also be examined for affinity at the serotonin 5-HT1A, 5-HT1B, 5-HT1C, 5-HT1D, and 5-HT2, alphal- and alpha2-adrenergic, and dopamine D1 and D2 receptors. Collaborative arrangements have been made to obtain functional measures of those compounds that have high affinity for the serotonin and dopamine receptor subtypes (effects on PI turnover and cAMP). For the lysergamides, conformational energy calculations will be performed, and pKa and log P values will also be determined. Hallucinogenic lysergamides have not been adequately studied in the past and it is anticipated that some quantitative combination of variables for the lysergamides, and a consideration of the conformational energies, may allow correlation with the in vivo behavioral potency, thus identifying the relative importance and the nature of the interaction of LSD-like ligands with the various monoamine receptors. A particular power of this approach is the use of diastereomeric lysergamides with chiral amide substituents. The two synthetic partial ergoline analogues will be used to test the hypotheses that: (1) a 2,3-dihydrobenzofuran can serve as an effective bioisostere for an indole and, (2) that ergolines may undergo a D-ring inversion on' binding to some monoamine receptors to present the unshared electron pair of the amino group on the upper, or beta-face of the ergoline molecule. These studies will lead to a greater understanding of the nature of the ligand-receptor interaction for the monoamine receptors studied, as well as to a better understanding of the relative importance of these particular monoamine receptors in the action of LSD and other hallucinogens.
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