Pergolide, terguride and N,N′-spacer-linked oligomers of both interact with 5-HT2A receptors of rat tail artery

Pergolide, terguride and N,N'-spacer-linked oligomers of both have been tested for their ability to interact with 5-hydroxytryptamine(HT)(2A) receptors of rat tail artery. Pergolide was a potent partial agonist (pEC(50) 7.5, E-max 55%) and antagonized 5-HT-induced contractions (pK(p) 7.2). Pergolide dimer 3 with a p-xylene spacer between the indole nitrogens (N-1) displayed somewhat lower agonist potency than pergolide (pEC(50) 7.0, E-max 55%, pK(p) 6.6). The contractile responses to pergolide and dimer 3 were antagonized by the 5-HT2A receptor antagonist ketanserin (pA(2) 9.4, 9.1). In contrast to pergolide dimer 3, pergolide dimers 5 and 9 with an alkyl and an aralkyl spacer between the piperidine nitrogens (N-6) lacked agonism and displayed low affinity at 5-HT2A receptors (pA(2) < 5.5). Terguride behaved as an insurmountable antagonist of 5-HT (pA(2) 8.4). Oligomers of terguride showed 5 to 50-fold lower affinity. It is concluded that pergolide and terguride show a high affinity for 5-HT2A receptors, but dimerization (oligomerization) of both drugs fails to increase affinity.